RU2601550C2 - Ketolide compounds - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention relates to used in medicine compound of formula I

where T denotes -C*H(R₁)-P-Q; R₁ denotes C₁-C₆alkyl optionally substituted OH or C₁-C₆alkoxy; P denotes a 5- or 6-member heteroaryl containing atoms of nitrogen, oxygen and sulphur; Q denotes a 5- or 6-member heteroaryl containing atoms of nitrogen, oxygen and sulphur; optionally substituted amino groups or hydroxy groups; P is connected to Q through carbon-carbon bond; and R₃ denotes a hydrogen atom.

EFFECT: there are presented new effective antibacterial compounds obtained new effective methods to create a based pharmaceutical compositions and treatment of bacterial infections.

32 cl, 4 tbl, 65 ex

Description

RELATED PATENT APPLICATIONS

This application claims the priority of India's final patent application No. 3352 / MUM / 2010, filed December 9, 2010, the disclosure of which is incorporated herein by reference in its entirety, as if it were completely rewritten in this document.

FIELD OF THE INVENTION

The invention relates to ketolide compounds of the formula (I) and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs and stereoisomers. The invention also relates to pharmaceutical compositions containing these compounds and methods for treating or preventing microbial infections using these compounds.

BACKGROUND OF THE INVENTION

Macrolides are a well-known family of antimicrobial agents. Erythromycin A, a 14-membered macrolide, was isolated in 1952 from Streptomyces erythraeus. Examples of macrolides used as therapeutic agents are roxithromycin, clarithromycin and azithromycin (azalide). Ketolides are semisynthetic derivatives of 14-membered cyclic macrolides characterized by the presence of a keto function at position 3 instead of the L-cladinose moiety present in the macrolactone ring. Examples of ketolides are telithromycin and cetromycin.

US Pat. No. 4,331,803 discloses a 6-O-methyl derivative of erythromycin, i.e. clarithromycin. US Pat. No. 4,349,545 discloses roxithromycin. US Pat. No. 4,517,359 discloses azithromycinazalide. Telithromycin is described in EP 680967 A1 and the corresponding US patent 5635485 and Bioorg. Med. Chem. Lett. 1999, 9 (21), 3075-3080. Another ketolid cetromycin (ABT 773) is disclosed in WO 98/09978 and J. Med. Chem. 2000, 43, 1045.

US patent N 6900183 describes 11,12-γ-lactone ketolides, including C-21 substituted cyano or amino derivatives of lactone. In patent applications, for example, US 2004/0077557 and PCT publications WO 02/16380, WO 03/42228, WO 03/072588 and WO 04/16634 disclosed 11,12-γ-lactone ketolides. In a co-examined PCT publication by the same authors WO 08/023248, several macrolides and ketolides are described.

SUMMARY OF THE INVENTION

In one general aspect, provided are compounds of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, or stereoisomer thereof,

Where

T is —C * H (R ₁ ) —PQ;

R ₁ is H or unsubstituted or substituted lower alkyl, cycloalkyl or aryl;

P represents a heteroaryl ring;

Q is an unsubstituted or substituted aryl or heteroaryl ring; and

P is attached to Q via a carbon-carbon bond; and

R ₃ represents a hydrogen or fluorine atom. Provided that if R ₁ is a hydrogen atom, then R ₃ is a fluorine atom.

In another general aspect, pharmaceutical compositions are provided comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally with one or more pharmaceutically acceptable excipients.

In another general aspect, a method for treating or preventing a microbial infection in a subject is provided, comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In another general aspect, a method is provided for treating a subject with a microorganism infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In another general aspect, a method for prophylactically treating a subject is provided, comprising administering to a subject at risk of infection caused by a microorganism a prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In another general aspect, there is provided a method of treating a subject with a microorganism infection, comprising administering to a subject in need of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally with one or more a pharmaceutically acceptable excipient.

In some other embodiments, a method is provided for prophylactically treating a subject, comprising administering to a subject at risk of infection caused by a microorganism, a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally with one or more a pharmaceutically acceptable excipient.

Details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the present invention will be apparent from the following description, including the claims.

DETAILED DESCRIPTION OF THE INVENTION

The following are links to typical variations and use a specific language to describe them. However, it should be understood that this does not imply any limitation on the scope of the invention. Changes and further modifications of the characteristic features of the invention illustrated here, as well as additional applications of the principles of the invention illustrated here, which may occur to a person skilled in the art, who owns this description, should be considered within the scope of this invention. It should be noted that used in this description and the attached claims, the singular form "a", "an" and "the" include the plural, unless otherwise understood.

Typically, the following definitions are used unless otherwise indicated.

The symbol * indicates a chiral center in formula (I) that has an R or S form or a mixture of both.

The term "stereoisomer" refers to compounds that have the same chemical composition, but differ in the arrangement of atoms and groups in space. These include enantiomers, diastereomers, geometric isomers, atropisomers and conformational isomers. Geometric isomers can occur if the compound contains a double bond or some other feature that gives the molecule a certain structural rigidity. The enantiomer is the stereoisomer of the parent molecule, which is an incompatible mirror image of the molecule. The diastereomer is the stereoisomer of the parent molecule, which has a shape that is not a mirror image of the parent molecule. The atropisomer is the conformation of the parent compound, which is converted to the parent compound only slowly by NMR or laboratory timeline. Conformational isomers (or conformers, or rotational isomers, or rotamers) are stereoisomers obtained by rotation around the σ-bond and are often rapidly interconvertible at room temperature. Racemic mixtures are also included in the scope of this invention. Some compounds of the present invention may have trans and cis isomers and geometric E and Z isomers. A wavy bond indicates that the compound may be present in the form of any of the E or Z isomers. Also, some of the compounds of this invention may exist as diastereomers. Furthermore, if the process for preparing the compounds of the invention provides a mixture of stereoisomers, these isomers can be resolved by conventional methods such as preparative chromatography and HPLC. Compounds can be obtained as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers.

The terms "polymorphs, solvates and hydrates" have the meanings discussed here. The compounds of the invention may exist in the form of various polymorphs, such as crystalline or amorphous forms, and as such should be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) that contain various amounts of water, for example, hydrate, hemihydrate and sesquihydrate. The compound may also form solvates with common organic solvents. Such solvates and hydrates are intended to be included within the scope of the present invention.

The term “lower alkyl” refers to straight chain or branched C ₁ -C ₆ alkyl hydrocarbon radicals containing from one to six carbon atoms. Examples of C ₁ -C ₆ alkyl radicals include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl and their branched isomers such as isopropyl, isobutyl or tert-butyl.

The term “cycloalkyl” refers to a C ₃ -C ₆ saturated carbocyclic radical containing from three to six carbon atoms. Examples of a C ₃ -C ₆ saturated carbocyclic radical include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "substituted lower alkyl" refers to substituted C ₁ -C ₆ alkyl, independently replacing one or two or three hydrogen atoms with groups F, Cl, Br, I, NO ₂ , NH ₂ , CN, OH, C ₁ - C ₆ alkoxy, alkylamino, dialkylamino, mercapto, formyl, carboxy, alkoxycarbonyl and carboxamide, aryl, heteroaryl, substituted aryl, substituted heteroaryl. Examples of such substitutions are fluoromethyl, difluoromethyl, trifluoromethyl, nitromethyl, aminomethyl, cyanomethyl, hydroxymethyl and the like. Examples of C ₁ -C ₆ alkoxy include methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, pentyloxy, hexyloxy.

The term “alkylamino” refers to a group having the structure —NH (C ₁ -C ₆ alkyl), wherein the C ₁ -C ₆ alkyl is as previously defined.

The term “dialkylamino” refers to a group having the structure —N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), wherein the C ₁ -C ₆ alkyl is as previously defined. Examples of dialkylamino include, but are not limited to, dimethylamino, diethylamino, methylethylamino and the like.

The term “aryl” refers to a mono- or bicyclic ring system, such as phenyl or naphthyl.

The term "heteroaryl" refers to mono, i.e. 5-6 membered, or bicyclic, i.e. a condensed aromatic ring system having at least one substitution of the carbon atom of the aromatic ring with an atom selected from the group consisting of N, O, S. For example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, triazolyl, triazinyl, furanyl, N-oxopyridyl and the like. Heteroaryl includes fused biaryl systems such as indolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzothienyl, N-oksohinolil, benzimidazolyl, benzopyranyl, benzoisothiazolyl, benzodiazinil, benzofurazanyl, indazolyl, indolizinyl, benzofuryl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl (such as furo [ 2,3-c] pyridinyl, furo [3,2-b] pyridinyl, furo [2,3-b] pyridinyl), naphthyridinyl, phthalazinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, thienothienyl, purinyl (for example, 9H-purine -1-yl, 6-amino-9H-purin-9-yl), pyridi yl-1H-pyrazol-1-yl and the like.

An aryl or heteroaryl group may be optionally substituted by independently replacing one or more hydrogen atoms with substituents selected from: C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, cyano, hydroxy, halogen, amino, formyl, carboxy, carboxamide, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ alkylcarbonyl, alkylamino, dialkylamino, mercapto, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylthio, arylthio, heteroarylthio or haloalkyl.

As used herein, the term “pharmaceutically acceptable salt” refers to one or more salts of the free base of the invention that possess the desired pharmacological activity of the free base and which are not biologically or otherwise undesirable. These salts are suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions and the like, and correspond to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. Describe pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. Salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable acid. These salts can be obtained from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, perchloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, oxalic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, para-toluenesulfonic acid, salicylic acid and the like. Also included are salts with various amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine or optically active isomers, or racemic mixtures thereof, or dipeptides, tripeptides and polypeptides derived from these monoamino acid units.

Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, glucocetate, glucoheptate, glucocetate, glucocetate, glucoceptate , hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propylate, propivalate tearat, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

Salts of the acid moiety in the compound can be prepared by reaction with a suitable base. Inorganic or organic base salts are also suitable salts. Inorganic bases are KOH, NaOH, Ca (OH) ₂ , Al (OH) ₃ . Organic base salts of basic amines, such as ethylamine, triethylamine, diethanolamine, ethylenediamine, guanidine, or heterocyclic amines, such as piperidine, hydroxyethylpyrrolidine, hydroxyethyl piperidine, morpholine, piperazine, N-methylpiperazine and the like, or optically basic amino acids pure and racemic isomers of arginine, lysine, histidine, tryptophan and the like. Other pharmaceutically acceptable salts include, where appropriate, salts of non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

The expression “therapeutically effective amount” means that amount of the compound (s) or pharmaceutical agent (s) that elicits a biological or medical reaction in the tissue system, animal or human being under the supervision of a researcher, veterinarian, doctor or other clinician, said reaction comprising relieving the symptoms of a disease or disorder being treated. The specific amount of active compound (s) or pharmaceutical agent (s) that is necessary to induce a biological or medical response depends on a number of factors, including, but not limited to, the diseases or disorders being treated, the active compound (s) or pharmaceutical the agent (s) that are administered, the route of administration and the condition of the patient.

As used herein, the terms “treat”, “treatment”, or “treatment” refer to the administration of a pharmaceutical composition or compound for prophylactic and / or therapeutic purposes. The term “prophylactic treatment” refers to the treatment of a subject who is not yet infected, but is susceptible or, in another way, is at risk of infection. The term "therapeutic treatment" refers to the treatment of a subject already suffering from an infection. Thus, in preferred embodiments, the treatment is the administration to a subject (for therapeutic or prophylactic purposes) of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof.

As used herein, the term “subject” refers to vertebrate and invertebrate animals, including mammals. The term “subject” includes a human, animal, bird, fish or amphibian. Typical non-limiting examples of “subjects” include humans, cats, dogs, horses, sheep, cattle, pigs, sheep, rats, mice, and guinea pigs.

As used herein, the term “microorganism” or “microbe” includes bacteria, fungi, protozoa, yeast, mold, or mildew.

As used herein, the term “infection” includes the presence of a microorganism in or on a subject that is relieved by inhibiting the growth of the microorganism. Essentially, the term “infection”, in addition to the presence of microorganisms, also refers to the normal flora, which is not desirable. The term "infection" includes an infection caused by bacteria, fungi, protozoa, yeast, mold, or mildew.

Typical non-limiting examples of infections include infections such as pneumonia, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis associated with infection with the following bacteria: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus or Peptostreptococcus; pharyngitis, rheumatic fever and glomerulonephritis associated with infection of Streptococcus pyogenes, group C and G streptococci, Clostridium diptheriae or Actinobacillus haemolyticum; respiratory infections associated with infections of Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenza or Chlamydia pneumoniae; uncomplicated infections of the skin and soft tissues, abscesses and osteomyelitis, and maternal fever associated with infection with Staphylococcus aureus, coagulase-positive staphylococci (e.g. S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, streptococcus CF (minute exposure streptococcus colonies), streptococcus viridans streptococci, Corynebacterium minutissimum, Clostridium or Bartonella henselae; uncomplicated acute urinary tract infections associated with infection with Staphylococcus saprophyticus or enterococcus species; urethritis and cervicitis; sexually transmitted diseases associated with infection of Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum or Neiserria gonorrheae; diseases caused by toxins associated with infection with S. aureus (food poisoning and toxic shock syndrome) or streptococcus groups A, B and C; ulcers associated with Helicobacter pylori infection; systemic febrile syndromes associated with Borrelia recurrentis infection; Lyme disease associated with Borrelia burgdorferi infection; conjunctivitis, keratitis and dacryocystitis associated with infection with species of Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenza or Listeria; disseminated diseases caused by mycobacterial avium complex (MAC) associated with infection of Mycobacterium avium or Mycobacterium intracellulare; gastroenteritis associated with Campylobacter jejuni infection; protozoal intestinal infections associated with infection by Cryptosporidium species; odontogenic infections associated with viridans streptococci infection; persistent cough associated with infection of Bordetella pertussis; gas gangrene associated with infection by Clostridium perfringens or Bacteroides species; atherosclerosis associated with infection of Helicobacter pylori or Chlamydia pneumoniae. Bacterial infections and protozoal infections and diseases that can be treated or prevented in animals that can be treated or prevented include the following: cattle respiratory infections associated with infection with P. haem., P. multocida, Mycoplasma bovis or Bordetella, intestinal infections cow diseases associated with infection with E. coli or protozoal infections (i.e., coccidia, Cryptosporidia, etc.); mastitis of dairy cows associated with infection by species of Staph. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella, species of Corynebacterium or Enterococcus; pig respiratory disease associated with infection with A. pleuro., P. multocida or Mycoplasma species; swine intestinal diseases associated with infection of E. coli, Lawsonia intracellularis, Salmonella or Serpulina hyodyisinteriae; ungulate rot of cows associated with infection by species of Fusobacterium; cows metritis associated with infection with E. coli; hairy warts in cows associated with infection with Fusobacterium necrophorum or Bacteroides nodosus; cow conjunctivitis associated with infection of Moraxella bovis; premature termination of pregnancy in cows associated with protozoal infections (e.g., neosporium); urinary tract infections in dogs and cats associated with infection with E. coli; skin and soft tissue infections in dogs and cats associated with Staph infection. epidermidis, Staph. intermedius, coagulase neg. Staph. or P. multocida; and dental or oral infections in dogs and cats associated with infection with Alcaligenes species, Bacteroides species, Clostridium species, Enterobacter, Eubacterium, Peptostreptococcus, Porphyromonas or Prevotella species.

In one general aspect, provided are compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, polymorphs or stereoisomers thereof

Where

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom; unsubstituted or substituted lower alkyl, cycloalkyl or aryl;

P represents a heteroaryl ring;

Q is an unsubstituted or substituted aryl or heteroaryl ring; and

P is attached to Q via a carbon-carbon bond; and

R ₃ represents a hydrogen or fluorine atom,

with the proviso that if R ₁ is a hydrogen atom, then R ₃ is a fluorine atom.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom;

R ₃ represents a fluorine atom,

P represents a 5-6 membered heteroaryl ring with up to three heteroatoms;

Q represents an unsubstituted or substituted aryl or a 5- or 6-membered heteroaryl ring; and

P is attached to Q via a carbon-carbon bond.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom;

R ₃ represents a fluorine atom,

P represents a 5-6 membered heteroaryl ring with up to three heteroatoms;

Q represents an unsubstituted or substituted aryl or a 5- or 6-membered heteroaryl ring with up to two nitrogen atoms; and

P is attached to Q via a carbon-carbon bond.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom;

R ₃ represents a fluorine atom,

P is a 5 membered heteroaryl ring, such as isoxazole or thiadiazole;

Q represents an unsubstituted or substituted aryl or a 6-membered heteroaryl ring with up to two nitrogen atoms; and

P is attached to Q via a carbon-carbon bond.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom;

R ₃ represents a fluorine atom,

P is a 6 membered heteroaryl ring, such as pyridine or pyrimidine;

Q represents an unsubstituted or substituted aryl or a 5- or 6-membered heteroaryl ring with heteroatoms in an amount of up to two; and

P is attached to Q via a carbon-carbon bond.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom;

R ₃ represents a fluorine atom,

P is a 5 membered heteroaryl ring, such as isoxazole or thiadiazole;

Q is unsubstituted or substituted pyridine or pyrimidine; and

P is attached to Q via a carbon-carbon bond.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom;

R ₃ represents a fluorine atom,

P is thiadiazole;

Q is unsubstituted or substituted pyridine or pyrimidine; and

P is attached to Q via a carbon-carbon bond.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom;

R ₃ represents a fluorine atom,

P is isoxazole;

Q is unsubstituted or substituted pyridine or pyrimidine; and

P is attached to Q via a carbon-carbon bond.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom;

R ₃ represents a fluorine atom,

P is thiadiazole;

Q is pyridine or pyrimidine; and

P is attached to Q via a carbon-carbon bond.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom;

R ₃ represents a fluorine atom,

P is isoxazole;

Q is pyridine or pyrimidine; and

P is attached to Q via a carbon-carbon bond.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom;

R ₃ represents a fluorine atom,

P is pyrimidine;

Q is unsubstituted or substituted 5-membered heteroaryl; and

P is attached to Q via a carbon-carbon bond.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom;

R ₃ represents a fluorine atom,

P is pyrimidine;

Q is isoxazole; and

P is attached to Q via a carbon-carbon bond.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ is unsubstituted or substituted lower alkyl, cycloalkyl or aryl;

P represents a heteroaryl ring;

Q is an unsubstituted or substituted aryl or heteroaryl ring; and

P is attached to Q via a carbon-carbon bond; and

R ₃ represents a hydrogen or fluorine atom.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ is unsubstituted or substituted lower alkyl;

P represents a heteroaryl ring;

Q is an unsubstituted or substituted aryl or heteroaryl ring; and

P is attached to Q via a carbon-carbon bond; and

R ₃ represents a hydrogen or fluorine atom.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ is unsubstituted or substituted lower alkyl;

P is a 5 membered heteroaryl ring with up to three heteroatoms;

Q is an unsubstituted or substituted aryl or heteroaryl ring; and

P is attached to Q via a carbon-carbon bond; and

R ₃ represents a hydrogen or fluorine atom.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ is unsubstituted or substituted lower alkyl;

P is a 5 membered heteroaryl ring with up to three heteroatoms;

Q represents an unsubstituted or substituted aryl or heteroaryl ring with up to two nitrogen atoms; and

P is attached to Q via a carbon-carbon bond; and

R ₃ represents a hydrogen or fluorine atom.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ is methyl;

P is a 5 membered heteroaryl ring with up to three heteroatoms;

Q represents an unsubstituted or substituted aryl or heteroaryl ring with up to two nitrogen atoms; and

P is attached to Q via a carbon-carbon bond; and

R ₃ represents a hydrogen or fluorine atom.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ is methyl;

P is a 5 membered heteroaryl ring, such as isoxazole or thiadiazole;

Q represents an unsubstituted or substituted aryl or heteroaryl ring with up to two nitrogen atoms; and

P is attached to Q via a carbon-carbon bond; and

R ₃ represents a hydrogen or fluorine atom.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ is methyl;

P is a 5 membered heteroaryl ring, such as isoxazole or thiadiazole;

Q is pyridine or pyrimidine; and

P is attached to Q via a carbon-carbon bond; and

R ₃ represents a hydrogen or fluorine atom.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ is methyl;

P is thiadiazole;

Q is pyridine or pyrimidine; and

P is attached to Q via a carbon-carbon bond; and

R ₃ represents a hydrogen or fluorine atom.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ is methyl;

P is isoxazole;

Q is pyridine or pyrimidine; and

P is attached to Q via a carbon-carbon bond; and

R ₃ represents a hydrogen or fluorine atom.

In some other embodiments, a compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, selected from:

the compounds of formula (I), where T is [3- (pyrimidin-2-yl) isoxazol-5-yl] -CH ₂ - and R ₃ is F;

the compounds of formula (I), where T is [5- (isoxazol-3-yl) pyrimidin-2-yl] -CH ₂ - and R ₃ is F;

the compounds of formula (I), where T is [5- (pyrimidin-2-yl) isoxazol-3-yl] -CH ₂ - and R ₃ is F;

compounds of formula (I), where T is [5- (2-aminopyridin-6-yl) isoxazol-3-yl] -CH ₂ - and R ₃ is F;

compounds of formula (I), where T is [5- (pyridin-2-yl) isoxazol-3-yl] -CH ₂ - and R ₃ is F;

compounds of formula (I), where T is [2- (2-aminopyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH ₂ - and R ₃ is F;

the compounds of formula (I), where T is [2- (pyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH ₂ - and R ₃ is F;

compounds of formula (I), where T is [2- (2-aminopyridin-5-yl) -1,3,4-thiadiazol-5-yl] -CH ₂ - and R ₃ is F;

compounds of formula (I), where T is [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH ₂ - and R ₃ is F;

the compounds of formula (I), where T is [5- (pyrazin-2-yl) isoxazol-3-yl] -CH ₂ - and R ₃ is F;

compounds of formula (I), where T is [2- (6-aminopyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH ₂ and R ₃ is F;

compounds of formula (I), where T is [2- (3-aminophenyl) -1,3,4-thiadiazol-5-yl] -CH ₂ - and R ₃ is F;

compounds of formula (I), where T is [2- (2-aminopyridin-6-yl) pyridin-6-yl] -CH ₂ - and R ₃ is F;

compounds of formula (I), where T is [5- (6-aminopyrimidin-2-yl) isoxazol-3-yl] -CH ₂ - and R ₃ is F;

compounds of formula (I), where T is (RS) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (R) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I) wherein T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

a compound of formula (I), wherein T is (RS) - [3- (pyridin-2-yl) isoxazol-5-yl] -CH (CH ₃₎ - and R ₃ is H;

a compound of formula (I), wherein T is (R) - [3- (pyridin-2-yl) isoxazol-5-yl] -CH (CH ₃₎ - and R ₃ is H;

compounds of formula (I) wherein T is (S) - [3- (pyridin-2-yl) isoxazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

a compound of formula (I), wherein T is (RS) - [5- (pyrimidin-2-yl) isoxazol-3-yl] -CH (CH ₃₎ - and R ₃ is H;

compounds of formula (I), where T is (R) - [5- (pyrimidin-2-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (S) - [5- (pyrimidin-2-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is H;

the compounds of formula (I), where T is (R) - [5- (pyridin-2-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (S) - [5- (pyridin-2-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (R) - [5- (pyridin-2-yl) isoxazol-3-yl] -CH (C ₂ H ₅ ) - and R ₃ is H;

the compounds of formula (I), where T is (S) - [5- (pyridin-2-yl) isoxazol-3-yl] -CH (C ₂ H ₅ ) - and R ₃ is H;

compounds of formula (I), where T is (RS) - [2- (pyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (R) - [2- (pyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (S) - [2- (pyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (S) - [2- (2-aminopyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;

compounds of formula (I), where T is (R) - [2- (2-aminopyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;

compounds of formula (I), where T is (RS) - [2- (2-aminopyridin-5-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;

compounds of formula (I), where T is (S) - [2- (2-aminopyridin-5-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;

compounds of formula (I), where T is (R) - [2- (2-aminopyridin-5-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;

compounds of formula (I), where T is (RS) - [2- (pyrazin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I) wherein T is (R) - [2- (pyrazin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (S) - [2- (pyrazin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (RS) - [2- (pyridin-2-yl) -1,3,4-oxadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (S) - [2- (3-aminophenyl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

the compounds of formula (I), where T is (S) - [2- (2-hydroxypyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;

compounds of formula (I), where T is (S) - [5- (isoxazol-3-yl) pyrimidin-2-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (S) - [5- (2-aminopyridin-6-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (S) - [2- (4-hydroxypyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;

compounds of formula (I), where T is (R) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₂ OH) - and R ₃ is H;

compounds of formula (I), where T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₂ OH) - and R ₃ is H;

the compounds of formula (I), where T is (RS) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (C ₂ H ₅ ) - and R ₃ is H ;

the compounds of formula (I), where T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (C ₂ H ₅ ) - and R ₃ is H ;

compounds of formula (I), where T is (R) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (C ₂ H ₅ ) - and R ₃ is H ;

compounds of formula (I), where T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is F;

compounds of formula (I), where T is (R) - [2- (2-aminopyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is F .

compounds of formula (I), where T is (S) - [2- (2-aminopyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is F ;

compounds of formula (I), where T is (S) - [2- (pyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is F;

compounds of formula (I), where T is (S) - [2- (pyrazin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is F;

compounds of formula (I), where T is (S) - [5- (pyrimidin-2-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is F;

compounds of formula (I), where T is (S) - [2- (3-aminophenyl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is F;

compounds of formula (I), where T is (S) - [5- (pyridin-2-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is F;

compounds of formula (I), where T is (S) - [5- (isoxazol-3-yl) pyrimidin-2-yl] -CH (CH ₃ ) - and R ₃ is F;

the compounds of formula (I), where T is (R) - [5- (isoxazol-3-yl) pyrimidin-2-yl] -CH (CH ₃ ) - and R ₃ is F; and

compounds of formula (I), where T is (S) - [5- (2-aminopyridin-6-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is F.

In some other embodiments, a compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, selected from:

the compounds of formula (I), where T is [5- (isoxazol-3-yl) pyrimidin-2-yl] -CH ₂ - and R ₃ is F;

compounds of formula (I), where T is [2- (pyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH ₂ - and R ₃ is F;

compounds of formula (I) wherein T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (S) - [2- (pyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (S) - [2- (2-aminopyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;

compounds of formula (I), where T is (S) - [2- (2-aminopyridin-5-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;

compounds of formula (I), where T is (S) - [5- (isoxazol-3-yl) pyrimidin-2-yl] -CH (CH ₃ ) - and R ₃ is H;

compounds of formula (I), where T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₂ OH) - and R ₃ is H;

compounds of formula (I), where T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (C ₂ H ₅ ) - and R ₃ is H ;

compounds of formula (I), where T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is F;

compounds of formula (I), where T is (S) - [2- (2-aminopyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is F ;

compounds of formula (I), where T is (S) - [2- (pyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is F;

compounds of formula (I), where T is (S) - [2- (3-aminophenyl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is F;

compounds of formula (I), where T is (S) - [5- (isoxazol-3-yl) pyrimidin-2-yl] -CH (CH ₃ ) - and R ₃ is F; and

compounds of formula (I), where T is (S) - [5- (2-aminopyridin-6-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is F.

In some other embodiments, compounds of formula (I) are provided wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ represents a hydrogen atom;

R ₃ represents a fluorine atom;

P is 1,3,4-thiadiazole or pyrimidine;

Q is pyrimidin-2-yl or isoxazol-3-yl; and

P is attached to Q via a carbon-carbon bond.

In some other embodiments, a compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, selected from:

(11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12,11- {hydroxycarbonyl- [EN - [(5-pyrimidin-2-yl- 1,3,4-thiadiazol-2-yl) methoxy] carboxamidino] methylene} erythromycin A;

(11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12,11- {hydroxycarbonyl- [EN - [(5-isoxazol-3-ylpyrimidine- 2-yl) methoxy] carboxamidino] methylene} erythromycin A.

In some other embodiments, a compound of formula (I) is provided, wherein:

T is —C * H (R ₁ ) —PQ;

R ₁ is methyl;

P is 1,3,4-thiadiazole;

Q is pyridin-2-yl or pyrimidin-2-yl; and

P is attached to Q via a carbon-carbon bond; and

R ₃ represents a hydrogen atom.

In some other embodiments, a compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, selected from:

(11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11- {oxycarbonyl- [EN- [1- (5-pyridin-2-yl-1, 3,4-thiadiazol-2-yl) - (S) -ethoxy] carboxamidino] methylene} erythromycin A;

(11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11- {hydroxycarbonyl- [EN- [1- (5-pyrimidin-2-yl-1, 3,4-thiadiazol-2-yl) - (S) -ethoxy] carboxamidino] methylene} erythromycin A.

In some other embodiments, a process for preparing a compound of formula (3rd) is provided.

including:

(i) converting a compound of formula (3-a) into a compound of formula (3-b);

(ii) converting a compound of formula (3-b) into a compound of formula (3-c);

(iii) converting a compound of formula (3-c) into a compound of formula (3-d)

(iv) converting a compound of formula (3-d) into a compound of formula (3-e).

In other embodiments, a method for producing a compound of formula (4) is provided.

including:

(i) conversion of 2-methylpyrimidin-4-carbaldehyde (4-a) to give a compound of formula (4-b);

(ii) converting a compound of formula (4-b) into a compound of formula (4-c);

(iii) converting a compound of formula (4-c) into a compound of formula (4-d); and

(iv) converting a compound of formula (4-d) into a compound of formula (4-e).

In some embodiments, a process for preparing a compound of formula (19-d) is provided.

including:

(i) reacting a compound of formula (19-a) with a compound of formula (19-b) to obtain a compound of formula (19-c).

(ii) converting a compound of formula (19-c) into a compound of formula (19-d).

In some embodiments, a process for preparing a compound of formula (15-f) is provided.

including;

(i) converting a compound of formula (15) into a compound of formula (15-b);

(ii) converting a compound of formula (15-b) into a compound of formula (15-c);

(iii) converting a compound of formula (15-c) into a compound of formula (15-d);

(iv) converting a compound of formula (15-d) into a compound of formula (15th); and

(v) converting a compound of formula (15-e) into a compound of formula (15-f).

In some embodiments, a process for preparing a compound of formula (16-d) is provided.

including:

(i) reacting pyrimidine-2-carbonyl chloride with a compound of formula (15-b) to obtain a compound of formula (16-a);

(ii) converting a compound of formula (16-a) into a compound of formula (16-b);

(iii) converting a compound of formula (16-b) into a compound of formula (16-c); and

(iv) converting a compound of formula (16-c) into a compound of formula (16-d).

In some embodiments, a process for preparing a compound of formula (17th) is provided.

including:

(i) converting a compound of formula (17-a) into a compound of formula (17-b)

(ii) converting a compound of formula (17-b) into a compound of formula (17-c)

(iii) converting a compound of formula (17-d) into a compound of formula (17-d); and

(iv) converting a compound of formula (17-d) into a compound of formula (17th).

In some other embodiments, a process for preparing a compound of formula (18th) is provided.

including:

(i) reacting a compound of formula (18-a) with a compound of formula (18-b) to obtain a compound of formula (18-c);

(ii) converting a compound of formula (18-c) into a compound of formula (18-d); and

(iii) converting a compound of formula (18-d) into a compound of formula (18th).

In some embodiments, a process for the preparation of a compound of formula (19-d ′) is provided.

including:

(i) reacting a compound of formula (19-a) with a compound of formula (19-b ′) to give a compound of formula (19-c ′); and

(ii) converting a compound of formula (19-d ′) into a compound of formula (19-d ′).

In some embodiments, a method for producing compounds of formula (I) is provided, wherein the variables have predetermined values, the method including a process that will be easier to understand in connection with the following synthesis schemes.

In some embodiments, pharmaceutical compositions are provided comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally with one or more pharmaceutically acceptable excipients.

The expression "pharmaceutically acceptable excipient" refers to a substance other than the active ingredient, and includes pharmaceutically acceptable carriers, diluents, stabilizers, binders, colorants, buffers, lubricants, disintegrants, surfactants, substances that promote

slip, plasticizers, fillers, diluents, emollients, wetting agents, etc. A pharmaceutically acceptable excipient often facilitates the delivery of the active ingredient. The type and amount of any excipient used will largely depend on the desired therapeutic response and other factors, such as route of administration, etc.

To provide a patient with an effective dose of the compounds of the invention, any suitable route of administration may be used. So, for example, you can use oral, rectal, vaginal, parenteral (subcutaneous, intramuscular, intravenous), nasal, transdermal, local and similar methods of administration. Suitable dosage forms include tablets, pills, powders, troches, dispersions, solutions, suspensions, emulsions, capsules, injectable preparations, plasters, ointments, creams, lotions, shampoos and the like.

In some embodiments, the pharmaceutical compositions of the invention are administered parenterally or orally.

In some embodiments, there is provided a method of treating or preventing a microbial infection in a subject, comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In some embodiments, a method is provided for treating a subject with a microorganism infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In some other embodiments, a prophylactic treatment method is provided for a subject, comprising administering to a subject at risk of infection caused by a microorganism a prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In some other embodiments, a method is provided for treating a subject with a microorganism infection, comprising administering to a subject in need of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally with one or more pharmaceutically acceptable filler.

In some other embodiments, the invention provides a method for prophylactically treating a subject, comprising administering to a subject at risk of infection caused by a microorganism, a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally with one or more pharmaceutically acceptable excipients.

The prophylactic or therapeutic dose of the ketolide compounds of formula (I) and their pharmaceutically acceptable salts in the treatment of acute or chronic diseases varies depending on the severity of the condition to be treated and the route of administration. In addition, the dose and, possibly, the frequency of administration of the dose also vary depending on the age, body weight and response of a particular patient. In general, the range of total daily doses for the compounds of the invention under the conditions described herein is from about 10 mg to about 5000 mg. In some cases, it may be necessary to apply doses whose size is beyond this range, which is clear to experts in this field.

In addition, it is noted that the clinician or attending physician knows how and when to interrupt, adjust or stop treatment in accordance with the individual response of the patient.

General techniques

According to Scheme 1, a heteroaryl aldoxime of formula 1-a is reacted with N-chlorosuccinamide or sodium hypochlorite in a suitable solvent, such as N, N-dimethylformamide or Ν, Ν-dimethylacetamide, at a temperature in the range of 25 to 35 ° C. to obtain the corresponding heteroaryl chlororamidoxime formulas 1-b.

Scheme 1

The compound of formula 1-b is treated with ethyl propiolate in the presence of an organic base, such as triethylamine, in a suitable solvent, such as toluene or xylene, at a temperature in the range of 25 to 50 ° C. to give the corresponding ethyl ester, which in turn is reduced using borohydride sodium in methanol or ethanol at a temperature of from 0 to 35 ° C, obtaining the corresponding methanol derivative of the formula 1-d. This intermediate is then reacted with methanesulfonyl chloride in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane or chloroform, at a temperature in the range of -5 to 35 ° C. to give the corresponding methanesulfonic acid ester of formula 1-e, which then subjected to interaction with lithium bromide in a suitable solvent, for example acetone ;, at a temperature in the range from 35 to 55 ° C, obtaining the corresponding intermediate bromide of the formula 1-f.

Scheme 2

According to Scheme 2, an ethynyl heteroaryl compound of formula 2 is reacted with ethyl chloroxamido acetate in the presence of an organic base, such as triethylamine, in a suitable solvent, such as toluene, at a temperature in the range of 80 to 95 ° C. to obtain the corresponding ethyl ester derivative of formula 2-b .

The 2-b ester derivative is reacted with a reducing agent, such as sodium borohydride, in a suitable solvent, such as methanol or ethanol, at a temperature in the range of 0 to 35 ° C. to obtain the corresponding methanol derivative of formula 2-c, which is reacted with methanesulfonyl chloride in the presence of an organic base such as triethylamine in a suitable solvent such as dichloromethane or chloroform, at a temperature in the range of -5 to 35 ° C. to give the corresponding methanesulfonyl ester acid, which is then reacted with lithium bromide in a suitable solvent, such as acetone, at a temperature in the range of 35 to 55 ° C., to obtain the corresponding methyl bromide derivative of formula 2-d.

Scheme 3

Compounds of formula 3-e are synthesized according to Scheme 3. Thus, an ester of formula 3-a is reacted with hydrazine or hydrazine hydrate in a suitable solvent, such as methanol or ethanol, at a temperature in the range of 25 to 85 ° C. to obtain the corresponding hydrazide derivative formulas 3-b.

The oxalyl chloride monoethyl ether is then treated in the presence of an organic base such as triethylamine in a suitable solvent such as dichloromethane or chloroform or tetrahydrofuran, at a temperature in the range of -5 to 35 ° C., followed by optionally replacing the solvent with a solvent selected from tetrahydrofuran or 1,4-dioxane, and the reaction mixture is treated with Lawesson's reagent at a temperature in the range of 40 to 70 ° C. to obtain the desired thiadiazole derivative of formula 3-c.

The ester (3-c) is reacted with a reducing agent such as sodium borohydride in a suitable solvent, ethanol or an aqueous ethanol solution at a temperature in the range of -5 to 35 ° C. to obtain the corresponding methanol derivative of formula 3-d.

Alcohol (3-e) is reacted with methanesulfonyl chloride in the presence of an organic base, such as triethylamine, in a suitable solvent, such as dichloromethane or chloroform, at a temperature in the range of -5 to 35 ° C. to give the corresponding mesylate derivative, which is then brought into reaction with lithium bromide in a suitable solvent, such as acetone, at a temperature in the range of 35 to 55 ° C. to obtain the corresponding bromide of formula 3-e.

Optionally, a heteroaryl-1,3,4-thiadiazolylmethyl bromide derivative of formula 3e is prepared by reacting a methanol intermediate (3-d) with carbon tetrabromide together with triphenylphosphine in a suitable solvent, such as dichloromethane, at a temperature in the range of 0 to 35 ° C .

Scheme 4

According to Scheme 4, 2-methylpyrimidine-5-carbaldehyde (4-a) is reacted with hydroxylamine hydrochloride in the presence of a base such as sodium carbonate or sodium bicarbonate or potassium carbonate in a suitable solvent such as methanol or ethanol or water, or their mixture, at a temperature in the range from 0 to 35 ° C, obtaining the corresponding oxime of 2-methylpyrimidine-5-carbaldehyde (4-b).

Compound 4-b is reacted with N-chlorosuccinamide or sodium hypochlorite in a suitable solvent, such as Ν, Ν-dimethylformamide or Ν, Ν-dimethylacetamide, at a temperature in the range of 0 to 35 ° C. to obtain the corresponding methyl-substituted pyrimidinylchlororamidoxime compound, which is further treated with trimethylsilylacetylene in a suitable solvent, such as diethyl ether, Ν, Ν-dimethylformamide or a mixture thereof, at a temperature in the range of -5 to 35 ° C. to give the corresponding 4-c compound.

Compound 4-c is converted to compound 4-d by reaction with a base, such as sodium carbonate or potassium carbonate or sodium bicarbonate, in a suitable solvent, such as methanol or ethanol, at a temperature in the range from 0 to 50 ° C.

Compound 4-d is reacted with N-bromosuccinamide in the presence of a radical initiator, such as benzoyl peroxide or azoisobutyronitrile (AIBN), in carbon tetrachloride at a temperature in the range from 65 to 80 ° C to obtain the corresponding isoxazolylpyrimidinylmethyl bromide - compound 4-е.

Scheme 5

According to Scheme 5, 2-bromo-6-N, N-di-tert-butoxycarbonylaminopyridine (5-a) is reacted with hexabutyl distannan in the presence of a palladium catalyst such as palladium tetrakis (triphenylphosphine) or bis (triphenylphosphine) palladium (II) dichloride, in a suitable solvent such as dimethoxyethane, DMF or toluene, at a temperature in the range of 80 to 90 ° C., to give the corresponding tributyltin-substituted pyridine derivative 5-b.

Compound 5-b is reacted with 2-bromopyridin-6-carbaldehyde using a catalyst such as palladium tetrakis (triphenylphosphine) in the presence of lithium chloride and a base such as triethylamine in toluene at a temperature in the range of 100 to 110 ° C obtaining the corresponding 5-c addition product.

Compound 5-c is reacted with a reducing agent, such as sodium borohydride, in a suitable solvent, such as tetrahydrofuran or ethanol or methanol, or aqueous ethanol, or a mixture thereof, at a temperature in the range of 25 to 35 ° C. to obtain the corresponding substituted pyridinyl methyl alcohol - compounds 5-d.

Compound 5-d is reacted with methanesulfonyl chloride in the presence of an organic base such as triethylamine in a suitable solvent such as dichloromethane or chloroform at a temperature of 0 to 25 ° C. to give the corresponding methanesulfonic acid ester and substituted pyridinyl methyl alcohol, which is then brought into reacting with lithium bromide in a suitable solvent, such as acetone, at a temperature in the range of 35 to 55 ° C. to obtain the corresponding substituted bispyridinylmethyl bromide - compound eniya 5th.

Scheme 6

Compound 6th is synthesized according to Scheme 6, wherein 5-bromo-2-benzoyloxymethylpyrimidine (6-a) is reacted with hexabutyldistannan in the presence of a palladium catalyst such as palladium tetrakis (triphenylphosphine) or bis (triphenylphosphine) palladium (II) dichloride, in a suitable solvent, such as toluene, dimethoxyethane or DMF, at a temperature in the range of 80 to 110 ° C., to give the corresponding tributyltin-substituted pyrimidine derivative 6-b.

Compound 6-b is reacted with 2-iodopyrazine using a catalyst such as bis (triphenylphosphine) palladium (II) dichloride or palladium tetrakis (triphenylphosphine) in the presence of a base such as triethylamine in DMF at a temperature in the range of 100 up to 110 ° C, obtaining the corresponding product accession 6-s.

Compound 6-c is saponified by stirring with a base such as sodium methylate in a suitable solvent such as methanol at a temperature in the range of 25 to 35 ° C. to give the corresponding substituted pyrimidinyl methyl alcohol — compound 6-d.

Compound 6-d is reacted with methanesulfonyl chloride in the presence of an organic base such as triethylamine in a suitable solvent such as dichloromethane or chloroform at a temperature of 0 to 25 ° C. to give the corresponding methanesulfonic acid ester and substituted pyrimidinyl methyl alcohol, which is then brought into reacting with lithium bromide in a suitable solvent, such as acetone, at a temperature in the range of 35 to 55 ° C. to obtain the corresponding substituted pyrimidinylmethyl bromide - soda eniya 6th.

Scheme 7

According to Scheme 7, a heteroaryl aldoxime of formula 7-a is reacted with N-chlorosuccinamide or sodium hypochlorite in a suitable solvent, such as N, N-dimethylformamide or Ν, Ν-dimethylacetamide, or a mixture thereof, at a temperature in the range of 25 to 35 ° C with the receipt of the corresponding heteroarylchloramidoxime - compound 7-b. It is then treated with ethyl propiolate in the presence of an organic base, such as triethylamine or diisopropylethylamine, in a suitable solvent, such as toluene or xylene, at a temperature in the range of 25 to 50 ° C. to give the corresponding ethyl ester of formula 7-c.

The ester intermediate is then reacted with a reducing agent such as sodium borohydride in a suitable solvent such as methanol or ethanol or tetrahydrofuran (THF), or a mixture thereof, at a temperature in the range of 0 to 35 ° C. to obtain the corresponding alcohol of formula 7 -d.

Alcohol (7-d) is reacted with an oxidizing agent such as Dess Martin periodinan, pyridinium chlorochromate (PCC) or pyridinium fluorochromate (PFC) in a suitable solvent such as dichloromethane or dichloroethane or chloroform, or a mixture thereof, at a temperature in the range of from 25 to 35 ° C to obtain the corresponding aldehyde derivative of the formula 7th. The aldehyde (7th) is reacted with methyl magnesium iodide in a suitable solvent, such as dichloromethane or dichloroethane, or chloroform, or tetrahydrofuran (THF), or a mixture thereof, at a temperature in the range from 0 to 10 ° C to obtain the corresponding alcohol (7 -f). It is converted to the corresponding 7-g bromomethyl derivative by reacting with methanesulfonyl chloride in the presence of a base such as triethylamine, isolating the corresponding alkyl sulfonate and treating it with lithium bromide in acetone at reflux temperature or optionally by reacting with carbon tetrabromide together with triphenylphosphine in a suitable solvent such as tetrahydrofuran (THF) at a temperature in the range of 10 to 35 ° C.

Scheme 8

According to Scheme 8, an ethynylheteroaryl derivative of formula 8-a is reacted with ethyl chloroxamidoacetate in the presence of an organic base, such as triethylamine, in a suitable solvent, such as toluene, at a temperature in the range of 80 to 110 ° C. to give the corresponding ester (8-b ) Then, it is reacted with methylmagnesium iodide in a suitable solvent, such as dichloromethane or dichloroethane, or chloroform, or tetrahydrofuran (THF), or a mixture thereof, at a temperature in the range from 0 to 10 ° C to obtain the corresponding ketone derivative (8th) . The ketone is reduced using sodium borohydride in a suitable solvent such as methanol or ethanol, or tetrahydrofuran (THF), or a mixture thereof, at a temperature in the range of 0 to 35 ° C. to obtain the corresponding alcohol derivative of formula 8-d.

The alcohol is converted to the corresponding mesylate derivative using methanesulfonyl chloride in the presence of an organic base such as triethylamine in a suitable solvent such as dichloromethane or dichloroethane or chloroform or tetrahydrofuran (THF), or a mixture thereof, at a temperature in the range of 0 to 15 ° C, which is then converted to the corresponding heteroarylisoxazolyl bromide of formula 8e by treatment with lithium bromide in a suitable solvent, such as acetone, at a temperature in the range of 45 to 55 ° C.

Scheme 9

According to Scheme 9, 2-picolinic acid hydrazide (9-a) is reacted with pyruvic acid chloride in the presence of an organic base such as triethylamine in dichloromethane at a temperature of from 0 to 5 ° C for 3 hours. Next, the reaction mixture was treated with para-toluenesulfonyl chloride and stirred at room temperature for 16 hours to obtain pyridine-1,3,4-oxadiazole - compound 9-b. Compound 9-b obtained in this way is reacted with a reducing agent with sodium borohydride in methanol or ethanol at a temperature of 35 ° C. to obtain pyridin-1,3,4-oxadiazolethanol (9-c). Compound 9-c is reacted with methanesulfonyl chloride in the presence of triethylamine in dichloromethane at a temperature in the range of 0 to 15 ° C. to obtain the corresponding methanesulfonyl ester of pyridinyl-1,3,4-oxadiazolylethanol, which is converted to the corresponding pyridine-1,3,4- oxadiazolylethyl bromide (9-d) by treating the sulfonyl ester with lithium bromide in acetone at reflux temperature.

Pattern 10

Chiral nosylate (10-f) is synthesized according to Scheme 10-a. The aminhydrochloride R-enantiomer, compound 10-a, is reacted with the vinylamide salt of dichloromethane and aqueous sodium hydroxide in acetonitrile at a temperature of 25 to 35 ° C to obtain the corresponding pyrimidinecarbaldehyde compound 10-b. Compound 10-b is reacted with hydroxylamine hydrochloride in the presence of sodium carbonate in aqueous methanol at ambient temperature to give the corresponding oxime, which is then reacted with N-chlorosuccinamide in DMF at the same temperature to give the corresponding chloramidate - compound 10-s. Compound 10-s is stirred with triethylamine and trimethylsilylacetylene in DMF and a diethyl ether mixture at a temperature of from -10 to 25 ° C to obtain the corresponding trimethylsilyl-protected isoxazolylpyrimidine compound, which, when treated with sodium carbonate in methanol at ambient temperature, gives isoxazolyl - pyrimidinyl - -d. The TBDMS group is removed by reacting compound 10-d with an HF reagent. pyridine in acetonitrile at a temperature of from 25 to 35 ° C to give compound 10th with free hydroxyl function. The hydroxyl group is then protected by reacting compound 10-e with para-nitrophenylsulfonyl chloride in the presence of triethylamine in dichloromethane at a temperature of 0 to 5 ° C to obtain the corresponding para-nitrophenylsulfonyl ether - compound 10-f.

Scheme 11

According to Scheme 11, a heteroarylcarboxylic acid alkyl ester of formula 11-a is reacted with hydrazine hydrate in ethanol at a temperature in the range of 40 to 85 ° C. to give the corresponding heteroaryl carboxylic acid hydrazide (11-b). Then, the hydrazide derivative is treated with oxalyl chloride monoethyl ether in the presence of triethylamine in dichloromethane or tetrahydrofuran at a temperature in the range from 5 to 30 ° C, after which the solvent is optionally replaced with tetrahydrofuran and the reaction mixture is treated with Lawesson's reagent at a temperature in the range from 40 to 70 ° C the corresponding heteroaryl-1,3,4-thiadiazolylcarboxylic acid alkyl ester (11-s). It is then reacted with methylmagnesium iodide in a suitable solvent, such as dichloromethane or tetrahydrofuran (THF), or a mixture thereof, preferably dichloromethane, at a temperature of from 0 to 10 ° C. to give the corresponding heteroaryl-1,3,4-thiadiazolylethane-2-one (11-d). The ketone is reduced using sodium borohydride in ethanol or methanol at a temperature in the range from 0 to 35 ° C to obtain the corresponding alcohol (11th). This alcohol (11th) is reacted with methanesulfonyl chloride in the presence of triethylamine in dichloromethane at a temperature in the range from -10 to 40 ° C, preferably from 0 to 15 ° C, to obtain the corresponding methanesulfonic acid ester and heteroaryl-1,3,4- thiadiazolylethanol, which is converted to the corresponding bromide (11-f) by treatment with lithium bromide in acetone at reflux temperature.

Pattern 12

According to Scheme 12, ethyl 2-bromobutyrate (12-a) is reacted with benzyl alcohol in the presence of potassium hydroxide in DMF at a temperature of 25 to 35 ° C for 3 hours to obtain ethyl 2-benzyloxybutyrate (12-b) . Compound 12-b is treated with hydrazine hydrate in ethanol at the boiling temperature under reflux to obtain the corresponding acid hydrazide - compound 12-c. Compound 12-c is treated with 2-picolinic acid in the presence of a dehydrating agent EDC together with HOBt and N-methylmorpholine in DMF at a temperature of from 0 to 30 ° C for 1 hour, obtaining an uncyclic compound 12-d. Then, compound 12-d is treated with Lawesson's reagent in tetrahydrofuran at the boiling temperature under reflux for 4 hours to obtain the corresponding pyridinyl-1,3,4-thiadiazolyl - compound 12th. Compound 12th was stirred with boron tribromide in dichloromethane at a temperature in the range of 0 to 5 ° C for 1 hour and then at 35 ° C overnight to obtain the corresponding pyridinyl-1,3,4-thiadiazolylpropanol - compound 12-f . Compound 12-f was treated with para-nitrophenylsulfonyl chloride in the presence of triethylamine in dichloromethane at a temperature in the range of 0 to 15 ° C. to give the corresponding 12-g para-nitrophenylsulfonic acid ester.

Pattern 13

According to Scheme 13, 13-a O-isopropylidenemethyl ether is reacted with hydrazine hydrate in methanol at a temperature of from 50 to 55 ° C overnight to obtain the corresponding acid hydrazide - compound 13-b. Compound 13-b is treated with 2-picolinic acid in the presence of a dehydrating agent EDC together with HOBt and N-methylmorpholine in DMF at a temperature of from 0 ° C to 30 ° C for 16 hours. to give compound 13-s. Then it is treated with Lawesson's reagent in tetrahydrofuran at a temperature of 35 ° C for 36 hours, obtaining the corresponding pyridinyl-1,3,4-thiadiazolyl - compound 13-d.

Then, the protected diol is stirred with aqueous hydrochloric acid in acetone at a temperature of 40 ° C for 6 hours to obtain the corresponding pyridinyl-1,3,4-thiadiazolylethanediol - compound 13th. Then, it is reacted with TBDMS chloride in the presence of triethylamine and DMAP in dichloromethane at a temperature of 0 to 35 ° C for 24 hours to obtain a mono-TBDMS-protected compound 13-f, which is mixed with para-nitrophenylsulfonyl chloride in the presence of triethylamine in dichloromethane at a temperature in the range from 0 to 5 ° C to obtain the corresponding para-nitrophenyl sulfonate ester - compound 13-g.

Scheme 14

Enantiomerically pure mesylate (14th) is first prepared by reacting racemic alcohol (14-a) with enantiomerically pure (S) -O-acetylmindic acid in the presence of dicyclohexylcarbodiimide and Ν, Ν-dimethylaminopyridine in dichloromethane at a temperature in the range from -15 to 5 ° C to obtain a mixture of diastereomers 14-b and 14-s.

This mixture of 14-b and 14-c is dissolved in methanol to give a clear solution and then cooled to 25 ° C. in order to selectively crystallize one 14-c diastereomer as a white solid. Compound 14-c is hydrolyzed by treatment with an aqueous solution of sodium hydroxide or potassium hydroxide in methanol at a temperature of from -15 to 5 ° C to obtain enantiomerically pure compound 14-d. Then, the alcohol (14-d) is reacted with methanesulfonyl chloride in the presence of triethylamine in dichloromethane at a temperature in the range of -10 to 5 ° C to obtain the enantiomerically pure corresponding methanesulfonic acid ester of 14th.

Scheme 15

According to Scheme 15, TBDMS-Cl is first introduced to protect commercially available D-methyl lactate to give compound 15-a, and then reacted with hydrazine hydrate in ethanol at reflux temperature to give the corresponding acid hydrazide — compound 15-b. Compound 15-b is reacted with 2-picolinic acid using an EDC dehydrating agent in the presence of N-methylmorpholine and HOBt in a solvent, such as DMF, at a temperature of 25 to 35 ° C. to give compound 15-c. Compound 15-c is cyclized by reacting it with Lawesson's reagent in THF at reflux temperature to obtain TBDMS-protected pyridinyl-1,3,4-thiadiazole — compound 15-d. Remove the TBDMS group from compound 15-d using a 2N aqueous solution of hydrochloric acid in acetonitrile at a temperature of 25 to 35 ° C. to give compound 15th. Compound 15th is reacted with para-nitrophenylsulfonyl chloride in the presence of triethylamine in dichloromethane at a temperature of 10 to 25 ° C. to give the R-enantiomer of para-nitrophenylsulfonic acid ester (nosylate) and pyridine-1,3,4-thiadiazole as compound 15 -f.

Pattern 16

According to Scheme 16, pyrimidine-2-carbonyl chloride (obtained from 2-cyanopyrimidine using an aqueous solution of sodium hydroxide, followed by treatment with thionyl chloride in toluene) is reacted with the R-enantiomer of TBDMS-protected D-lactic acid hydrazide (15-b) in toluene at temperature from 10 to 15 ° C for 1 hour., getting the connection 16-a. Compound 16-a is cyclized by reaction with Lawesson's reagent in THF at reflux temperature to give TBDMS-protected pyrimidinyl-1,3,4-thiadiazolyl — compound 16-b. The TBDMS group is removed with a 2N aqueous solution of hydrochloric acid in acetonitrile at a temperature of 25 to 35 ° C. to give a 16-c compound, which is reacted with para-nitrophenylsulfonyl chloride in the presence of triethylamine in dichloromethane at a temperature of from 0 to 5 ° C., the chiral pure (R) ester of para-nitrophenylsulfonic acid (nosylate) and pyrimidine-1,3,4-thiadiazole is compound 16-d.

Scheme 17

According to scheme 17, the interaction (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-hydroxy) carboxamidino] methylene} erythromycin A (17-a) with triethylbenzylammonium bromide (obtained in situ by mixing benzyl bromide and triethylamine in tetrahydrofuran) in the presence of powdered potassium hydroxide in tetrahydrofuran at a temperature in the range from 20 to 35 ° C, yielding the corresponding amide benzyl amide oxyl amide connection 17-b.

Alternatively, compound 17-b is prepared by reacting amidoximmacrolide 17-c with benzyl bromide in the presence of a base, such as potassium hydride or potassium carbonate, or potassium tert-butylate, in the presence of a phase transfer catalyst such as 18-crown-6-ether, in a solvent such as toluene or xylene, or acetone, or methyl ethyl ketone, at a temperature in the range of 20 ° C to 35 ° C.

Compound 17-b is oxidized under standard conditions using either NCS and DMS oxidizing agents (Kim-Corey reagent) or Dess-Martin periodinan reagent, in a suitable solvent such as dichloromethane or dichloroethane or chloroform, at a temperature in the range of -50 to 10 ° C, obtaining (benzyl ether) amidoximeketolide - compound 17-s. Compound 17-c is fluorinated by reacting it with a fluorinating agent, such as N-fluorodibenzenesulfonimide (NFSI) or Selectfluor, in the presence of a base, such as lithium tert-butylate or sodium tert-butylate, in a suitable solvent such as Ν, Ν-dimethylformamide (DMF), Ν, Ν-dimethylacetamide (DMAA) or tetrahydrofuran (THF), at a temperature in the range of -40 to 0 ° C to obtain the corresponding fluorinated ketolide - compound 17-d, which is then subjected to hydrogenolysis using 20% palladium hydroxide , or 10% palladium on carbon, or their a mixture, in the presence of a hydrogen source, such as hydrogen gas under pressure, in a solvent, such as methanol or ethanol, or ethyl acetate, or a mixture thereof, at a temperature in the range of 20 to 50 ° C. to obtain fluorinated ketolide - compound 17th.

General method for the synthesis of ketolides according to the invention:

According to Scheme 18, the amidoxime of formula 18-a is reacted with the corresponding racemic or enantiomerically pure bromide, mesylate, tosylate or nosylate derivative of formula 18-b in the presence of a suitable organic base such as potassium hydride or potassium tert-butylate, or an inorganic base such such as potassium hydroxide, with a phase transfer catalyst such as 18-crown-6-ether, in a suitable solvent such as toluene, at a temperature in the range of -10 to 50 ° C. to give the ether derivative of formula 18-c.

It is then oxidized under Cori-Kim oxidation conditions (NCS and DMS) or by means of a Dess-Martin periodinan reagent, in a suitable solvent such as dichloromethane or dichloroethane or chloroform, at a temperature in the range of −50 to 10 ° C., giving 2 '-O-triethylsilyl-protected ketolide of formula 18-d.

It is then reacted with a suitable silyl deprotecting agent, such as pyridine hydrofluoride, tetrabutylammonium fluoride, an aqueous solution of hydrochloric acid, in a suitable solvent, such as acetonitrile or tetrahydrofuran, or dioxane, at a temperature in the range of 0 to 40 ° C. to obtain a ketolide derived formula (18th).

A ketolide of formula 18th (if the Q ring carries a Boc-NH type substituent) is optionally treated with pyridine hydrofluoride or trifluoroacetic acid in acetonitrile to give the corresponding amino acid derivative.

Compound 18th (if the Q ring carries an OBn substituent) is optionally hydrogenolized using palladium on carbon in a hydrogen atmosphere under pressure in a solvent such as methanol to give the corresponding hydroxyl derivative.

According to Scheme 19, amidoxime 19-a is reacted with the corresponding racemic or enantiomerically pure bromide, mesylate, tosylate or nosylate derivative of a heteroaryl of formula 19-b in the presence of a suitable organic base, such as potassium hydride or potassium tert-butylate, or an inorganic base, such such as potassium hydroxide, with an interfacial transfer catalyst such as 18-crown-6-ether, in a suitable solvent such as toluene, at a temperature in the range of -10 to 50 ° C. to give the corresponding ether derivative of the formula 19-s.

Which is then reacted with a suitable silyl deprotecting agent, such as pyridine hydrofluoride, tetrabutylammonium fluoride, an aqueous solution of hydrochloric acid, in a suitable solvent, such as acetonitrile or tetrahydrofuran, or dioxane, at a temperature in the range of 0 to 40 ° C. to obtain compounds 19-d.

In addition, compound 19-d 'was prepared in a similar manner by reacting 19-a with 19-b' to give 19-c ', followed by the conversion of 19-c' to 19-d '.

Compound 19-d or 19-d '(if the Q ring carries a substituent such as Boc-NH-or di-Boc-N) is optionally treated with pyridine hydrofluoride or trifluoroacetic acid in acetonitrile to give the corresponding amino derivative.

Compounds 19-d or 19-d ′ (if the Q ring has a substituent such as OBn) are optionally hydrogenated using palladium on carbon in a hydrogen atmosphere under pressure in a solvent such as methanol to give the corresponding hydroxyl derivative.

EXPERIMENTAL PART

Preparation 1: 2- (5-bromomethylisoxazol-3-yl) pyridine

Stage 1: pyridin-2-imidoyl chloride

A mixture of ethyl 2-pyridinaldoxime (15 g) and N-chlorosuccinamide (25 g) in DMF (30 ml) was stirred at 30 ° C for 2 hours. The reaction mixture was quenched with ice water (150 ml). The suspension is filtered and the wet cake washed with a small amount of water to give the title pure compound in an amount of 7 g (55%) as a white solid. MS (m / z): 157 (M + 1).

Stage 2: 2- (5-ethoxycarbonylisoxazol-3-yl) pyridine

Ethyl propiolate (10 g) was added to a mixture of pyridine-2-imidoyl chloride (15 g) and triethylamine (25 ml) in toluene (150 ml), stirred at 30 ° C for 0.5 hour. The progress of the reaction is monitored by TLC. The reaction was quenched with water (100 ml). The layers are separated. The organic layer is dried over sodium sulfate. The layer was evaporated in vacuo to give a wet mass. The crude mass was purified by silica gel column chromatography to give the title compound in an amount of 8.2 g (62%) as a liquid. The compound is characterized by proton NMR. ¹ H-NMR (CDCl ₃ ) δ: 1.39-1.42 (t, 3H), 4.41-4.46 (d, 2H), 7.34-7.37 (m, 1H), 7 55 (s, 1H), 7.78-7.82 (dt, 1H), 8.08-8.1 (d, 1H), 8.67-8.68 (d, 1H).

Stage 3: 2- (5-hydroxymethylisoxazol-3-yl) pyridine

To a mixture of 2- (5-ethoxycarbonylisoxazol-3-yl) pyridine (6.5 g) in ethanol (80 ml), sodium borohydride (2 g) was added in portions at 30 ° C. The mixture was stirred at 30 ° C for 1.5 hours. The progress of the reaction is monitored by TLC. After consumption of the starting material, an aqueous solution of ammonium chloride is added. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water and concentrated in vacuo to give the title compound in an amount of 7.7 g. It was purified by silica gel column chromatography to obtain the title compound in an amount of 4.5 g (85%) as an off-white solid matter. ¹ H-NMR (DMSO-d ₆ ) δ: 4.61-4.63 (d, 2H), 5.68-5.71 (t, 1H), 6.86 (s, 1H), 7.46 -7.49 (m, 1H), 7.90-7.94 (m, 1H), 7.98-8.0 (d, 1H), 8.68-8.69 (d, 1H).

Stage 4: 2- (5-methanesulfonyloxymethylisoxazol-3-yl) pyridine

To a mixture of 2- (5-hydroxymethylisoxazol-3-yl) pyridine (4.0 g) and triethylamine (6.5 ml) in dichloromethane (40 ml) was added methanesulfonyl chloride (2.8 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour. The reaction is quenched by adding water, and the layers are separated. The aqueous layer was extracted with dichloromethane (40 ml × 2). The combined organic layer was washed with an aqueous solution of sodium bicarbonate, then with water and evaporated in vacuo to give the title compound in an amount of 5.1 g (84%) as a semi-solid, which was used without purification for the next reaction.

Stage 5: 2- (5-bromomethylisoxadiazol-3-yl) pyridine

A mixture of 2- (5-methanesulfonyloxymethylisoxazol-3-yl) pyridine (5.0 g) and lithium bromide (3.4 g) in acetone (50 ml) was stirred at reflux for 2 hours. The reaction mixture was evaporated in vacuo to give a crude mass, which was triturated with chilled water (50 ml) to give a suspension. The suspension was filtered with suction to give the title compound in an amount of 3.1 g (85%). MS (m / z): 255.1 (M + 2).

Preparation 2: 2- (3-bromomethylisoxazol-5-yl) pyrimidine

Stage 1: 2- (3-ethoxycarbonylisoxazol-5-yl) pyrimidine

To a mixture of 2-ethynylpyrimidine (28 g) and ethyl chloroxamidoacetate (45 g) in toluene (340 ml) was added triethylamine (42 ml) at 90 ° C and stirred for 0.5 hour. The progress of the reaction is monitored by TLC. The reaction mixture was allowed to cool to 30 ° C and water was added. The organic layer is separated. The organic layer was evaporated in vacuo and the crude mass was triturated with n-hexane. The suspension was filtered and the wet cake was washed with a small amount of n-hexane to give the title compound in an amount of 35.1 g (59%) as a cream-colored solid. MS (m / z): 220.1 (M + 1).

Stage 2: 2- (3-hydroxymethylisoxazol-5-yl) pyrimidine

To a mixture of 2- (3-ethoxycarbonylisoxazol-5-yl) pyrimidine (35 g) in a mixture of ethanol: THF = 2: 1 v / v. (525 ml) was added portionwise sodium borohydride (7.5 g) at 0 ° C. The mixture was stirred at 30 ° C for 4 hours. The reaction mixture was evaporated in vacuo to give a residue and added to the residue (150 ml). The resulting suspension was extracted with ethyl acetate (4.5 L). The combined organic layers were washed with water and concentrated in vacuo to give a wet weight of 23 g, which was recrystallized from ethanol to give the title compound in an amount of 15.1 g (53%) as a pale yellow solid. MS (m / z): 178.1 (M + 1).

Stage 3: 2- (3-methanesulfonyloxymethylisoxazol-5-yl) pyrimidine

To a mixture of 2- (3-hydroxymethylisoxazol-5-yl) pyrimidine (14 g) and triethylamine (22 ml) in dichloromethane (400 ml) was added methanesulfonyl chloride (7.2 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 0.5 hour. The reaction is quenched by adding water, and the layers are separated. The organic layer was evaporated in vacuo to give the title compound in an amount of 19.7 g (97.7%) as a yellow solid. It is used as such in the next step.

Stage 4: 2- (3-bromomethylisoxazol-5-yl) pyrimidine

A mixture of 2- (3-methanesulfonyloxymethylisoxazol-5-yl) pyrimidine (19 g) and lithium bromide (13 g) in acetone (190 ml) was stirred at 30 ° C for 2 hours. The progress of the reaction is monitored by TLC. The reaction mixture was evaporated in vacuo to give a crude mass which, while stirring with water (150 ml), gave a suspension. Filtration of the suspension with suction gives the title compound in an amount of 15.2 g (75.3%) as a solid. MS (m / z): 239.9 and 241.9 (M + 1).

Preparation 3: 2- (5-bromomethyl-1,3,4-thiadiazol-2-yl) pyridine

Stage 1: pyridine-2-carboxylic acid hydrazide

A mixture of pyridine-2-carboxylic acid ethyl ester (90 g) and hydrazine (60 g) in ethanol (400 ml) was stirred at 80 ° C for 4 hours. The solvent was evaporated in vacuo to give a crude mass. The crude mass was stirred with diethyl ether, the suspension was filtered, and the wet cake was washed with a small amount of ethanol (50 ml) to obtain the title compound in an amount of 76 g (93%) as a white solid. MS (m / z): 138 (M + 1).

Stage 2: 2- (5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl) pyridine

To a mixture of pyridine-2-carboxylic acid hydrazide (76 g) and triethylamine (155 ml) in dichloromethane (600 ml) was added monoethyl oxalyl chloride (80 g) over a period of 0.5 hour. at 0 ° C. The reaction mixture was stirred for 2 hours. The reaction was quenched by adding water (100 ml), the layers were separated, and the organic layer was washed with an aqueous solution of sodium bicarbonate (100 ml). The organic layer was evaporated in vacuo to give a wet mass of 110 g. To the wet mass in tetrahydrofuran (500 ml) was added Laisson's reagent (208 g) and the mixture was stirred at 60 ° C for 4 hours. The solvent is evaporated and the crude mass is triturated with a mixture of dichloromethane-ether. The suspension is filtered and the wet cake washed with a small amount of methanol (100 ml) to obtain the title compound in an amount of 45 g (35% after 2 steps) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.37-1.38 (t, 3H), 4.30-4.38 (q, 2H), 7.51-7.54 (m, 1H), 7 89-7.92 (m, 1H); 8.26-8.28 (d, 1H); 8.59-8.60 (d, 1H). MS (m / z): 236 (M + 1).

Stage 3: 2- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) pyridine

To a mixture of 2- (5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl) pyridine (8 g) in ethanol (80 ml) was added portionwise sodium borohydride (2.51 g) at 30 ° C. The mixture was stirred at 30 ° C for 2 hours. The solvent was evaporated in vacuo to give a crude mass. Water (100 ml) was added to the crude mass and extracted with dichloromethane (200 ml × 2). The combined organic layers were washed with water and concentrated in vacuo to afford the title compound in an amount of 6.1 g (92%).

¹ H-NMR (CDCl ₃ ) δ: 4.87-4.88 (d, 2H), 6.264-6.26 (br s, 1H), 7.54-7.57 (m, 1H), 7 98-8.02 (m, 1H); 8.22-8.24 (d, 1H); 8.67 (d, 1H). MS (m / z): 194 (M + 1).

Stage 4: 2- (5-methanesulfonyloxymethyl-1,3,4-thiadiazol-2-yl) pyridine

To a mixture of 2- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) pyridine (6 g) and triethylamine (13.1 ml) in dichloromethane (150 ml) was added methanesulfonyl chloride (5.31 g) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour. The reaction is quenched by adding water, and the layers are separated. The aqueous layer was extracted with dichloromethane (50 ml × 2). The combined organic layer was washed with aqueous sodium bicarbonate, then with water and evaporated in vacuo to give the title compound in an amount of 7.5 g (88%) as an oil. MS (m / z): 272 (M + 1).

Stage 5: 2- (5-bromomethyl-1,3,4-thiadiazol-2-yl) pyridine

A suspension of 2- (5-methanesulfonyloxymethyl-1,3,4-thiadiazol-2-yl) pyridine (7.5 g) and lithium bromide (3.84 g) in acetone (75 ml) was stirred at reflux temperature in within 1 hour. The progress of the reaction is monitored by TLC. The reaction mixture was evaporated in vacuo to give a crude mass. The wet mass is mixed with ice water to obtain a suspension. The solid was suction filtered to give the title compound in an amount of 6.5 g (92%) as a light brownish solid.

¹ H-NMR (CDCl ₃ ) δ: 5.16 (s, 1H), 7.57-7.6 (m, 1H), 8.01-8.04 (m, 1H), 8.24-8 26 (d, 1H); 8.69-8.7 (d, 1H); MS (m / z): 255 (M-1).

Preparation 4: 2-bromomethyl-5-isoxazol-3-ylpyrimidine

Stage 1: 2-methyl-5-formylpyrimidine

To a mixture of a salt of vinamidium diperchlorate (310 g, obtained according to the procedure described in the Collection Czechoslov Chem. Commun. Vol. 30, 1965) and acetamidine hydrochloride (106 g) in acetonitrile (2.5 L) at 30 ° C, 50% by weight is added dropwise at 30 ° C ./about. an aqueous solution of sodium hydroxide (96.8 g, dissolved in 97 ml of water) for 2 hours. with stirring. The suspension is stirred for 3 hours. and adjust the pH of the reaction mixture to 7 by adding acetic acid (~ 147 ml). The solid is filtered off and washed with acetonitrile (750 ml). The filtrate was evaporated in vacuo to give a residue. The residue was stirred with water (750 ml) and the mixture was extracted with dichloromethane (300 ml × 5). The layers were separated and the organic layer was evaporated to give the title compound in an amount of 52 g (52%) as a low melting solid.

¹ H-NMR (DMSO-d ₆ ) δ: 11.08 (br s, 1H), 10.08 (s, 1H), 9.09 (s, 2H), 2.69 (s, 3H).

Stage 2: oxime 2-methylpyrimidine-5-carbaldehyde

To a mixture of 2-methyl-5-formylpyrimidine (180 g) and hydroxylamine hydrochloride (128 g) in 50% v / v. aqueous methanol (3600 ml) sodium carbonate (94 g) was added. The reaction mixture was stirred at 30 ° C for 0.5 hour. The resulting suspension was cooled and filtered at −10 ° C. to give a single isomer of the title compound in an amount of 113.5 g (56%) as a solid.

¹ H-NMR (DMSO-d ₆ ) δ: 11.64 (s, 1H), 8.83 (s, 2H), 8.14 (s, 1H), 2.60 (s, 3H).

Further processing of the filtrate, for example, evaporation and removal of salt, gives a mixture of isomers in an amount of 51 g, which can be used for the next interaction.

Stage 3: 2-methyl-5- (5-trimethylsilylethynylisoxazol-3-yl) pyrimidine

To a solution of 2-methylpyrimidin-5-carbaldehyde oxime (145 g) in DMF (435 ml) was added portionwise N-chlorosuccinamide (169.6 g) at 30 ° C. over 0.5 hour. When TLC indicated completion of the reaction, diethyl ether (1450 ml) was added. The reaction mixture is cooled to a temperature of from -5 to 0 ° C. Triethylamine (589 ml) was added to the cooled reaction mixture, followed by trimethylsilylacetylene (450 ml). The mixture was stirred at -5 ° C for another 1 hour. The separated solid is filtered off with suction. The filtrate was washed with water (300 ml × 4), then with brine (500 ml) and the organic layer was concentrated in vacuo to give a solid in an amount of 158 g, which was used as such for further interaction.

Stage 4: 2-methyl-5-isoxazol-3-ylpyrimidine

To a mixture of 2-methyl-5- (5-trimethylsilylethynylisoxazol-3-yl) pyrimidine (158 g) in methanol (1450 ml) was added sodium bicarbonate (177 g). The reaction mixture was stirred at 40 ° C for 1 hour. The reaction mixture is filtered. The resulting solid was washed with ethyl acetate, and the filtrate was evaporated in vacuo to give a residue. The residue was stirred with water (800 ml) and extracted with dichloromethane (500 ml × 3). The layers were separated and the organic layer was evaporated to give a residue (133 g) which, after column chromatography on silica gel, gave the title compound in an amount of 79 g, 46.4% yield after three steps.

¹ H-NMR (DMSO-d ₆ ) δ: 9.15 (s, 2H), 9.09 (d, 1H), 7.27 (d, 1H), 2.67 (s, 3H). MS (m / z): 162 (M + 1).

Stage 5: 2-bromomethyl-5-isoxazol-3-ylpyrimidine

A mixture of 2-methyl-5-isoxazol-3-yl-pyrimidine (30 g), N-bromosuccinamide (49.8 g) and 98% benzoyl peroxide (13.54 g) in carbon tetrachloride (1200 ml) is heated to a temperature of 75 ° C . The reaction mixture was stirred at 75 ° C for 24 hours. The reaction mixture is filtered with suction at a temperature of 25 to 35 ° C. The solid is washed with carbon tetrachloride (400 ml). The filtrate was washed with saturated aqueous sodium bicarbonate (400 ml × 2) and evaporated in vacuo to give crude material (52 g), which, after column chromatography on silica gel, gave the title compound in an amount of 14 g (40%), dibromo-substituted compound in the amount of 16.8 g and the starting material in the amount of 6.5 g

¹ H-NMR (DMSO-d ₆ ) δ: 9.30 (s, 2H), 9.13 (s, 1H), 7.32 (d, 1H), 4.74 (s, 2H).

Preparation 5: 2-di- (tert-butyloxycarbonyl) amino-6- (2-bromomethylpyridin-6-yl) pyridine

Stage 1: 2-di- (tert-butyloxycarbonyl) amino-6-tributylstannylpyridine

To a solution of 2-bromo-6-N, N-di-tert-butyloxycarbonylaminopyridine (13 g) in dimethoxyethane (260 ml) was added hexabutyldistannan (20.21 g), followed by palladium tetrakis (triphenylphosphine) (2.01 g) at 25 ° C and the resulting mixture is degassed for 30 minutes The reaction mixture is heated with stirring at a temperature of 80 ° C for 24 hours. The reaction mixture was cooled to ambient temperature and filtered through celite. The filtrate was stirred with water (250 ml) and extracted with ethyl acetate (150 ml × 3). The combined organic extract was washed with water (100 ml × 2), dried over Na ₂ SO ₄ . Evaporation of the solvents in vacuo afforded the title product as an oil (17.8 g) in 87% yield, which was used as such for the next reaction. MS (m / z): 584.1 (M + H).

Stage 2: 2-di- (tert-butyloxycarbonyl) amino-6- (2-formylpyridin-6-yl) pyridine

Suspension of 2-di- (tert-butyloxycarbonyl) amino-6-tributylstannylpyridine (15.3 g), 2-bromopyridin-6-carbaldehyde (7.0 g), triethylamine (10.60 g), palladium tetrakis (triphenylphosphine) (1.51 g) and lithium chloride (2.9 g) in toluene (140 ml) are degassed for 0.5 hour. at 25 ° C. The suspension is heated under reflux for 6 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was stirred with water (250 ml) and extracted with ethyl acetate (100 ml × 2). The combined organic extracts were dried over Na ₂ SO ₄ and evaporated in vacuo. The resulting crude mass was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound in an amount of 2.0 g in 19.1% yield. MS (m / z): 400.1 (M + H).

Stage 3: 2-di- (tert-butyloxycarbonyl) amino-6- (2-hydroxymethylpyridin-6-yl) pyridine

A solution of 2-di- (tert-butyloxycarbonyl) amino-6- (2-formylpyridin-6-yl) pyridine (1.9 g) in a mixture of tetrahydrofuran: methanol (1: 1, 20 ml) is treated with sodium borohydride (200 mg) in portions at a temperature of 25 to 35 ° C. When TLC showed complete consumption of the starting material, the solution was concentrated in vacuo. The crude mass was stirred with water (25 ml) and extracted with ethyl acetate (50 ml × 2). The combined organic extract was washed with saturated sodium bicarbonate solution (25 ml × 2), then with brine (25 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude mass. It was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound in an amount of 1.5 g in 79% yield. MS (m / z): 402.1 (M + H) ⁺ .

Stage 4: 2-di- (tert-butyloxycarbonyl) amino-6- (2-methanesulfonyloxymethylpyridin-6-yl) pyridine

A solution of 2-di- (tert-butyloxycarbonyl) amino-6- (2-hydroxymethylpyridin-6-yl) pyridine (1.5 g) and triethylamine (1.13 g) in dichloromethane (15 ml) is cooled to -5 ° C and treated with methanesulfonyl chloride (0.395 g). When TLC indicated completion of the reaction, water (10 ml) and then dichloromethane (50 ml) were added to the mixture. The organic layer was separated and washed with water (25 ml × 2), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound in an amount of 1.6 g in 90% yield, which was used as such in the next step. MS (m / z) (M + 1): 480.1.

Stage 5: 2-di- (tert-butyloxycarbonyl) amino-6- (2-bromomethylpyridin-6-yl) pyridine

A suspension of 2-di- (tert-butyloxycarbonyl) amino-6- (2-methanesulfonyloxymethylpyridin-6-yl) pyridine (1.6 g) and lithium bromide (435 mg) in acetone (17 ml) is heated under reflux in within 3 hours. When TLC indicated completion of the reaction, the reaction mixture was cooled to ambient temperature. The suspension is filtered with suction and concentrated in vacuo. The resulting residue was stirred with water (25 ml) and extracted with ethyl acetate (30 ml × 2). The combined organic extracts were washed with brine (25 ml) and dried over Na ₂ SO ₄ . The organic layer was concentrated in vacuo to give a wet mass, which was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound in an amount of 1.1 g with a yield of 70%. MS (m / z) (M + H): 465.2.

Preparation 6: (RS) -2- (5- (1-bromoethyl) isoxazol-3-yl) pyridine

Stage 1: pyridin-2-imidoyl chloride

A mixture of pyridine-2-carbaldehyde oxime (15 g) and N-chlorosuccinamide (25 g) in DMF (30 ml) was stirred at 30 ° C for 2 hours. The reaction mixture was cooled with ice water (150 ml). The suspension is filtered and the wet cake washed with a small amount of water to give the title pure compound in an amount of 7 g (55%) as a white solid. MS (m / z) 157 (M + 1).

Stage 2: 2- (5-ethoxycarbonylisoxazol-3-yl) pyridine

Ethyl propiolate (10 g) was added to a mixture of pyridine-2-imidoyl chloride (15 g) and triethylamine (25 ml) in toluene (150 ml), and the mixture was stirred at 30 ° C for 0.5 hour. The progress of the reaction is monitored by TLC. The reaction was quenched with water (100 ml). The layers are separated. The organic layer is dried over sodium sulfate. Evaporate the mixture in vacuo to give a wet mass. The crude mass was purified by silica gel column chromatography to give the title compound in an amount of 8.2 g (62%) as a liquid.

¹ H-NMR (CDCl ₃ ) δ: 1.39-1.42 (t, 3H), 4.41-4.46 (q, 2H), 7.34-7.37 (m, 1H), 7 55 (s, 1H), 7.78-7.82 (dt, 1H), 8.08-8.1 (d, 1H), 8.67-8.68 (d, 1H).

Stage 3: 2- (5-hydroxymethylisoxazol-3-yl) pyridine

To a mixture of 2- (5-ethoxycarbonylisoxazol-3-yl) pyridine (6.5 g) in ethanol (80 ml), sodium borohydride (2 g) was added in portions at 30 ° C. The mixture was stirred at 30 ° C for 1.5 hours. The progress of the reaction is monitored by TLC. While consuming ethyl ether, an aqueous solution of ammonium chloride is added. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water and concentrated in vacuo to give the title compound in an amount of 7.7 g. It was purified by silica gel column chromatography to obtain the title compound in an amount of 4.5 g (85%) as an off-white solid matter.

¹ H-NMR (DMSO-d ₆ ) δ: 4.61-4.63 (d, 2H), 5.68-5.71 (t, 1H), 6.86 (s, 1H), 7.46 -7.49 (m, 1H), 7.90-7.94 (m, 1H), 7.98-8.0 (d, 1H), 8.68-8.69 (d, 1H).

Stage 4: 2- (5-formylisoxazol-3-yl) pyridine

To a mixture of 2- (5-hydroxymethylisoxazol-3-yl) pyridine in dichloromethane (30 ml), Dess-Martin periodanane reagent (15% solution in dichloromethane, 51 ml) was added at 30 ° C. The reaction mixture was stirred at 30 ° C for 0.5 hour. The progress of the reaction is monitored by TLC. The reaction is quenched by adding an aqueous solution of sodium thiosulfate and sodium bicarbonate 1: 1. The layers are separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was evaporated in vacuo to give the title aldehyde in an amount of 3 g (quantitative yield).

¹ H-NMR (CDCl ₃ ) δ: 7.61 (s, 1H), 7.66-7.7 (t, 1H), 7.98-8.1 (d, 1H), 8.68-8 7 (d, 1H); 10.01 (s, 1H).

Stage 5: (RS) -2- (5- (1-hydroxyethyl) isoxazol-3-yl) pyridine

To a mixture of 2- (5-formylisoxazol-3-yl) pyridine (3 g) in THF (30 ml) was added methylmagnesium iodide (19 ml, 1.4 M solution in THF) at a temperature of 0 ° C for 15 min. The reaction mixture was stirred for 1.5 hours. and controlled by TLC. The reaction was quenched by adding an aqueous solution of ammonium chloride (20 ml), and extracted with ethyl acetate (100 ml × 2). The combined organic layers were washed with water and evaporated in vacuo to give 1.9 g of a wet mass, which was purified by silica gel column chromatography to obtain the title compound in an amount of 1.0 g (42%) as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.62-1.64 (d, 3H), 3.14 (s, 1H), 5.04-5.07 (q, 1H), 6.86 (s , 1H), 7.33-7.36 (m, 1H), 7.77-7.81 (dt, 1H), 8.03-8.05 (d, 1H), 8.66-8.68 (d, 1H).

Stage 6: (RS) -2- (5- (1-bromoethyl) isoxazol-3-yl) pyridine

To a mixture of (RS) -2- (5- (1-hydroxyethyl) isoxazol-3-yl) pyridine (0.9 g) and triphenylphosphine (1.77 g) in dichloromethane (20 ml), carbon tetrabromide is added at 0 ° C. (6 g). The reaction mixture was stirred at 30 ° C for 2.5 hours. The progress of the reaction is monitored by TLC. The reaction is quenched by adding water, and the layers are separated. The combined organic extract was washed with brine and evaporated in vacuo to give 1.7 g of a wet weight, which was purified by silica gel column chromatography to give the title compound in an amount of 0.8 g (65%).

¹ H-NMR (CDCl ₃₎ δ: 2,09-2,11 (d, 3H), 5,2-5,25 (q, 1H), 6,94 (c, 1H), 7,32-7 36 (m, 1H); 7.76-7.81 (m, 1H); 8.05-8.08 (t, 1H); 8.66-8.67 (d, 1H). MS: M + 1 = 254.1.

Preparation 7: (RS) -2- (3- (1-bromoethyl) isoxazol-5-yl) pyrimidine

Stage 1: 2- (3-ethoxycarbonylisoxazol-5-yl) pyrimidine

To a mixture of 2-ethynylpyrimidine (28 g) and ethyl chloroxamidoacetate (45 g) in toluene (340 ml), triethylamine (42 ml) was added at 90 ° C and stirred for 0.5 hour. The progress of the reaction is monitored by TLC. The reaction mixture was allowed to cool to 30 ° C and water was added. The organic layer is separated. The solvent was evaporated in vacuo and the crude mass was triturated with n-hexane. The suspension is filtered and the wet cake washed with a small amount of n-hexane to give the title compound in an amount of 35.1 g (59%) as a cream-colored solid. MS (m / z): 220.1 (M + 1).

Stage 2: 2- (3- (1-oxoethyl) isoxazol-5-yl) pyrimidine

To a mixture of THF: toluene (6.5 ml: 5 ml), triethylamine (16.3 ml) was added, followed by methyl magnesium iodide (28.6 ml, 1.4 M solution in THF) at 0 ° C. To the reaction mixture was added at 0 ° C 2- (3-ethoxycarbonylisoxazol-5-yl) pyrimidine (2.0 g) dissolved in toluene (35 ml) over 15 minutes. The reaction mixture was stirred for 2 hours. Quench the reaction by adding 1N aqueous hydrochloric acid (43 ml). The mixture was extracted with toluene. The combined organic layers were washed with saturated sodium bicarbonate and then with water. The organic layer was evaporated in vacuo to give a wet mass which, after purification by column chromatography on silica gel, afforded the title compound in an amount of 1.2 g (70%) as a solid.

¹ H-NMR (DMSO-d ₆ ) δ: 9.00 (d, 2H), 7.62 (t, 1H), 7.41 (s, 1H), 2.63 (s, 3H).

Stage 3: (RS) -2- (3- (1-hydroxyethyl) isoxazol-5-yl) pyrimidine

To a mixture of 2- (3- (1-oxoethyl) isoxazol-5-yl) pyrimidine (1.2 g) in methanol (20 ml) was added portionwise sodium borohydride (0.485 g) at 0 ° C. The mixture was stirred at 30 ° C for 2 hours. The reaction mixture was evaporated in vacuo to give a residue. The residue was stirred with water and extracted with ethyl acetate (25 ml × 3). The combined organic layers were washed with aqueous sodium bicarbonate and then with water, and concentrated in vacuo to afford the title compound in an amount of 1.1 g (91%). It is used without purification for the next interaction.

Stage 4: (RS) -2- (3- (1-bromoethyl) isoxazol-5-yl) pyrimidine

To a mixture of (RS) -2- (3- (1-hydroxymethyl) isoxazol-5-yl) pyrimidine (1.1 g) in dichloromethane (20 ml), carbon tetrabromide (7.64 g) was added, followed by triphenylphosphine (1 , 8 g) at 0 ° C. The reaction mixture was stirred at 0 ° C for 0.5 hour. and at 30 ° C for 2 hours. The reaction mixture was evaporated in vacuo to give a crude mass which, after column chromatography on silica gel, gave the title compound in an amount of 0.7 g (50%) as a solid.

¹ H-NMR (DMSO-d ₆ ) δ: 8.96 (d, 2H), 7.59-7.61 (t, 1H), 7.42 (s, 1H), 5.51-5.56 (q, 1H), 2.01-2.03 (d, 3H).

Preparation 8: (RS) -2- [5- (1-bromoethyl) -1,3,4-thiadiazol-2-yl] pyridine

Stage 1: pyridine-2-carboxylic acid hydrazide

A mixture of pyridine-2-carboxylic acid ethyl ester (90 g) and hydrazine (60 g) in ethanol (400 ml) was stirred at 80 ° C for 4 hours. The solvent was evaporated to give a wet mass. The mass was stirred with diethyl ether, and the suspension was filtered, and the wet cake was washed with a small amount of ethanol (50 ml) to obtain the title compound in an amount of 76 g (93%) as a white solid. MS (m / z): 138 (M + 1).

Stage 2: 2- (5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl) pyridine

To a mixture of pyridine-2-carboxylic acid hydrazide (76 g) and triethylamine (155 ml) in dichloromethane (600 ml), monoethyl oxalyl chloride (80 g) was added at 0 ° C over 0.5 hour. The reaction mixture was stirred for 2 hours. The progress of the reaction is monitored by TLC. The reaction was quenched by adding water (100 ml), the layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (100 ml). The organic layer was evaporated in vacuo to give a wet mass of 110 g. To the wet mass in tetrahydrofuran (500 ml) was added Laisson's reagent (208 g) and the mixture was stirred at 60 ° C for 4 hours. The solvent is evaporated and the crude mass is triturated with a mixture of dichloromethane-ether. The suspension is filtered and the wet cake washed with a small amount of methanol (100 ml) to obtain the title compound in an amount of 45 g (35% after 2 steps) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.37-1.38 (t, 3H), 4.30-4.38 (q, 2H), 7.51-7.54 (m, 1H), 7 89-7.92 (m, 1H); 8.26-8.28 (d, 1H); 8.59-8.60 (d, 1H). MS (m / z): 236 (M + 1).

Stage 3: 2- [5- (1-oxoethyl) -1,3,4-thiadiazol-2-yl] pyridine

To a mixture of 2- (5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl) pyridine (2 g) in THF (40 ml) was added methylmagnesium iodide (15 ml, 1.4 M solution in THF) at -40 ° C for 15 minutes The reaction mixture was stirred for 2 hours. at -40 ° C. The mixture was quenched by adding an aqueous solution of ammonium chloride (20 g) and stirred at 0 ° C for 10 minutes. The mixture was extracted with ethyl acetate (100 ml × 2). The combined organic layers were washed with water and evaporated in vacuo to afford the title compound in an amount of 1.5 g (86%) as an off-white solid.

¹ H-NMR (CDCl ₃ ) δ: 2.84 (s, 3H), 7.25-7.46 (m, 1H), 7.86-7.9 (m, 1H), 8.39-8 41 (d, 1H); 8.67-8.68 (d, 1H). MS (m / z): 206 (M + 1).

Stage 4: (RS) -2- [5- (1-hydroxyethyl) -1,3,4-thiadiazol-2-yl] pyridine

To a mixture of 2- [5- (1-oxoethyl) -1,3,4-thiadiazol-2-yl] pyridine (1.5 g) in methanol (25 ml), sodium borohydride (0.2 g) was added in portions at 30 ° C. The mixture is stirred for 2 hours. The progress of the reaction is monitored by TLC. The solvent was evaporated in vacuo and water (20 ml) was added. The mixture was extracted with ethyl acetate (100 ml × 2). The combined organic layers were washed with water and concentrated in vacuo to afford the title compound in an amount of 1.0 g (67%). It is used without purification for the next interaction. MS (m / z): 208 (M + 1).

Stage 5: (RS) -2- [5- (1-methanesulfonyloxyethyl) -1,3,4-thiadiazol-2-yl] pyridine

To a mixture of (RS) -2- (5- (1-hydroxyethyl) -1,3,4-thiadiazol-2-yl) pyridine (1.0 g) and triethylamine (2 ml) in dichloromethane (50 ml) was added methanesulfonyl chloride (0.9 g) at -10 ° C. The reaction mixture was stirred for 1 hour. The reaction is quenched by adding water, and the layers are separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with an aqueous solution of sodium bicarbonate, then with water and evaporated in vacuo to give the title compound in an amount of 1.0 g (73%) as an oil. MS (m / z): 286 (M + 1).

Stage 6: (RS) -2- [5- (1-bromoethyl) -1,3,4-thiadiazol-2-yl] pyridine

A mixture of (RS) -2- [5- (1-methanesulfonyloxyethyl) -1,3,4-thiadiazol-2-yl] pyridine (1.0 g) and lithium bromide (0.5 g) in acetone (20 ml) stirred at the boil under reflux for 1 hour. The reaction mixture was evaporated in vacuo to give a crude mass. The wet mass is stirred with ice water and extracted with dichloromethane (50 ml × 2). The combined organic layer was evaporated in vacuo to give the title compound in an amount of 0.8 g (85%) as an oil.

¹ H-NMR (CDCl ₃ ) δ: 2.2 (d, 2H), 5.51-5.57 (q, 1H), 7.38-7.41 (m, 1H), 7.83-7 87 (m, 1H); 8.32-8.34 (d, 1H); 8.63-8.64 (d, 1H); MS (m / z): 272 (M + 2).

Preparation 9: (R) -2- [5- (1-methanesulfonyloxyethyl) -1,3,4-thiadiazol-2-yl] pyridine

Stage 1: (R) -2- [5- (1-hydroxyethyl) -1,3,4-thiadiazol-2-yl] pyridine

To a mixture of (RS) -2- (5- (1-hydroxyethyl) -1,3,4-thiadiazol-2-yl) pyridine (7.5 g) and Ν, Ν-dimethylaminopyridine (0.5 g) was added at -10 ° C (R) -O-acetylmindic acid (7.1 g) and dichloromethane (150 ml) and a solution of dicyclohexylcarbodiimide (11.19 g) in dichloromethane (25 ml) was added. The reaction mixture was stirred for 1 hour. The reaction mixture was filtered with suction and the filtrate was evaporated in vacuo to give a residue, which was purified by silica gel column chromatography to obtain a mixture of two diastereomers in an amount of 10.0 g as a semi-solid. HPLC ratio diastereomer 2: diastereomer 1 = 42.46: 42.11. MS (m / z): 384 (M + 1).

A mixture of two diastereomers (10 g), obtained as described above, is stirred in methanol (25 ml) to obtain a clear solution. The reaction mixture was allowed to stir at 25 ° C for 0.5 hour. for precipitation. The solid was filtered off with suction and the wet cake was washed with methanol (5 ml). The wet solid (5 g) was suspended in methanol (15 ml). The mixture was stirred for 0.5 hour. and filtered with suction to give a solid. This solid was dried to give diastereomer-2 in an amount of 3.8 g as a solid. The filtrate is enriched in diastereomer-1. HPLC ratio of diastereomer-2: diastereomer-1 in the form of solids = 99.5: 0.5. MS (m / z): 384 (M + 1). ¹ H-NMR (CDCl ₃ ) δ: 1.79-1.81 (d, 3H), 2.23 (s, 3H), 5.96 (s, 1H), 6.29-6.33 (q , 1H), 7.55-7.58 (m, 1H), 7.76-7.80 (m, 1H), 7.91-7.93 (d, 1H), 8.01-8.04 (d, 1H). HPLC ratio of diastereomer-2: diastereomer-1 (from filtrate) = 21.23: 56.35. MS (m / z): 384 (M + 1).

The chiral pure diastereomer-2 obtained as described above (3.8 g) was dissolved in methanol (40 ml) and KOH (1.1 g dissolved in 4 ml of water) was added to the reaction mixture at -5 ° C. The reaction mixture was stirred at -5 ° C for 2 hours. The solvent was evaporated. The pH of the reaction mixture was adjusted to 4-5 using 2N aqueous hydrochloric acid. The mixture was extracted with dichloromethane (100 ml × 2). The combined organic layer was washed with saturated sodium bicarbonate solution. The layers were separated and evaporated in vacuo to give a chirally pure R-enantiomer in an amount of 2.1 g with a chiral purity of 99.11 according to HPLC.

¹ H NMR (CDCl ₃ ) δ: 1.42-1.6 (d, 3H), 5.19-5.24 (q, 1H), 7.45-7.48 (m, 1H), 7, 86-7.91 (m, 1H), 8.13-8.15 (d, 1H), 8.54 (br s, 1H), 8.77-8.78 (d, 1H). MS (m / z): 208 (M + 1). [α] D ₂₅ = + 15,33 ° (c 0,5, CHCl _3).

Stage 2: (R) -2- (5-methanesulfonyloxymethyl-1,3,4-thiadiazol-2-yl] pyridine

To a mixture of (R) -2- [5- (1-hydroxyethyl) -1,3,4-thiadiazol-2-yl] pyridine (2.0 g) and triethylamine (4.18 ml) in dichloromethane (100 ml) methanesulfonyl chloride (1.6 g) was added at -10 ° C. The reaction mixture was stirred at -10 ° C for 1 hour. The reaction is quenched by adding water, and the layers are separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with an aqueous sodium bicarbonate solution, then with water and evaporated in vacuo to give the title compound in an amount of 2.4 g (87%) with a chiral purity of 98.66% according to HPLC. MS (m / z): 286 (M + 1).

Preparation 10: (R) -2- [5- (1-nosyloxyethyl) -1,3,4-thiadiazol-2-yl] pyridine from methyl D-lactate

Step 1: Preparation of R-2- (tert-butyldimethylsilyloxy) propionic acid hydrazide

A mixture of R-2- (tert-butyldimethylsilyloxy) propionic acid (417 g) and hydrazine (144 g) in ethanol (400 ml) was stirred at 80 ° C for 4 hours. The solvent was evaporated to give a wet mass. The crude mass was stirred with water (150 ml) and extracted with ethyl acetate (800 ml × 2). The organic layer was dried over sodium sulfate and evaporated in vacuo to give the title compound in an amount of 417 g as a liquid in quantitative yield. MS (m / z): 219.2 (M + 1), GC purity: 76.48% (RT-14.14).

Stage 2: obtaining N '- [2- (tert-butyldimethylsilyloxy) propionyl] hydrazide R-pyridine-2-carboxylic acid

To a mixture of 2-picolinic acid (258 g) and R-2- (tert-butyldimethylsilyloxy) propionic acid hydrazide (415 g) in DMF (1000 ml) was added EDC hydrochloride (546 g), followed by N-methylmorpholine (418 ml) in 0.5 hour. at temperatures from 0 to 5 ° C. HOBt (29 g) was added in one portion. More DMF (245 ml) was added. The resulting suspension is stirred for 2 hours. at 25 ° C. The reaction mixture was poured into water (7000 ml) with stirring and extracted with ethyl acetate (4000 ml × 2). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to give a syrup of the title compound in an amount of 602 g in 98% yield. MS (m / z): 325.2 (M + 1).

Step 3: Preparation of R-2- {5- [1- (tert-butyldimethylsilyloxy) ethyl] -1,3,4-thiadiazol-2-yl} pyridine

A mixture of N '- [2- (tert-butyldimethylsilyloxy) propionyl] hydrazide R-pyridine-2-carboxylic acid (600 g) and Lawesson's reagent (448 g) in THF (1800 ml) was refluxed for 16 hours. with stirring. The reaction mixture was cooled to 25 ° C and poured into an aqueous solution of sodium bicarbonate (prepared from 366 g of sodium bicarbonate and 3000 ml of water) with stirring. The mixture was extracted with ethyl acetate (2000 ml × 2). The combined organic layer was washed with water (2000 ml) and dried over sodium sulfate. The organic layer was evaporated in vacuo to give the title compound in an amount of 570 g as a syrup in 95.3% yield. MS (m / z): 322.2 (M + 1), GC purity: 89.68% (RT 28.80).

Stage 4: obtaining R-1- (5-pyridin-2-yl- [1,3,4] thiadiazol-2-yl) ethanol

To a mixture of R-2- {5- [1- (tert-butyldimethylsilyloxy) ethyl] -1,3,4-thiadiazol-2-yl} pyridine (568 g) in acetonitrile (1800 ml) was added in one portion a 2N aqueous solution of hydrochloric acid (1800 ml) with stirring at 32 ° C. The mixture was stirred for 19 hours. The reaction mixture was poured into an aqueous solution of sodium carbonate (obtained by dissolving 560 g of sodium carbonate in 1800 ml of water) with stirring. The organic layer is separated. The aqueous layer was extracted with ethyl acetate (1000 ml × 2). The combined organic layer was dried over sodium sulfate and concentrated to give a semi-solid in an amount of 400 g, which was purified by stirring in ethyl acetate (400 ml) and filtering the resulting suspension to obtain the title compound in an amount of 230 g with a yield of 63% as a solid . MS (m / z): 208 (M + 1), chemical purity: 99.83% (RT 14.82).

Step 5: Preparation of R-5- (1-nosyloxyethyl) -1,3,4-thiadiazol-2-ylpyridine

To a mixture of R-1- (5-pyridin-2-yl- [1,3,4] thiadiazol-2-yl) ethanol (228 g) and triethylamine (230 ml) in dichloromethane (2000 ml) was added at 10 ° C and stirring a solution of para-nitrophenylsulfonyl chloride (246 g) dissolved in dichloromethane (500 ml). The reaction mixture was stirred for 2 hours. at 25 ° C. Water (2000 ml) and dichloromethane (1000 ml) are added to the resulting yellow suspension with stirring. The layers were separated and dried over sodium sulfate to give a brown solid in an amount of 514 g. This solid was stirred in a mixture of dichloromethane (250 ml) and diethyl ether (500 ml) at 30 ° C. The suspension was filtered with suction and washed with dichloromethane: diethyl ether (1: 2 ratio, 300 ml), the solid was dried in vacuo to give the title compound in an amount of 410 g as a pale yellow solid in 95% yield. MS (m / z): 393.0 (M + 1), chemical purity = 97.67%, chiral purity = 99.97%, [α] _D ²⁵ = + 135.79 (s = 0.5% in acetonitrile).

Getting 11:

(11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N- hydroxy) carboxamidino] methylene} erythromycin A

Step 1: Preparation of (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-benzyloxy) carboxamidino] methylene} erythromycin A

To a solution of triethylamine (4.5 ml) in THF (170 ml), benzyl bromide (3.1 ml) was added via syringe at 30 ° C. The mixture was stirred for 4 hours to give a suspension. To the suspension was added in one portion (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-hydroxy) carboxamidino ] methylene} erythromycin A (17 g), followed by powdered potassium hydroxide (1.57 g) in one portion. The reaction mixture was stirred for 3.5 hours. at 30 ° C. After monitoring by TLC, the reaction mixture was filtered with suction, removing salts. The filtrate was concentrated in vacuo to dryness at a temperature below 45 ° C, yielding 19 g of powder. It is stirred with chilled water (180 ml) for 5 hours to obtain a suspension. The solid was suction filtered and air dried to give the title compound in an amount of 17.8 g (93.8%) as a light yellow solid (HPLC purity 96.62%). MS (m / z): 876.2 (M + 1).

Step 2: Preparation of (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N- benzyloxy) carboxamidino] methylene} erythromycin A

To a stirred solution of N-chlorosuccinimide (7.5 g) in dichloromethane (75 ml) was added dimethyl sulfide (4.8 ml) at -15 ° C. The reaction mixture was stirred at -15 ° C for 1 hour. The product from step 1 (17 g) dissolved in dichloromethane (35 ml) was added to the reaction mixture at -40 ° C. The resulting reaction mixture was stirred at -40 ° C for 3 hours. Triethylamine (6.8 ml) was added and stirred overnight at 30 ° C. The reaction mixture was diluted with ethyl acetate (220 ml) and washed with a 0.5 M aqueous sodium hydroxide solution (100 ml). The organic layer was separated and washed with brine. The organic layer was concentrated in vacuo to dryness to obtain 14 g of powder. This powder was stirred with chilled water (140 ml) for 5 hours to give a suspension. The suspension is filtered and dried in air, obtaining 14 g of a pale yellow powder. This powder was stirred in methanol (42 ml) and filtered to obtain 11.2 g (66%) of the title compound as a white solid (HPLC purity 97.3%). MS (m / z): 874.2 (M + 1).

Step 3: Preparation of (11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E - (N-benzyloxy) carboxamidino] methylene} erythromycin A

To a solution of the product from step 2 (11 g) in DMF (110 ml) was added in portions over 30 minutes. lithium tert-butylate (1.51 g) as a solid at -15 ° C and N-fluorodibenzenesulfonimide (NFSI, 4.19 g) dissolved in DMF (40 ml) in 30 minutes. at -15 ° C. The reaction mixture was stirred for 0.5 hour. at -15 ° C. An aqueous solution of ammonium chloride (13 g in 750 ml of water) was added to the reaction mixture with stirring. The suspension is stirred for 0.5 hour. and filtered with suction. The solid was dissolved in ethyl acetate (200 ml) and washed with a 0.5 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, evaporated to dryness in vacuo to give the title compound as a solid in an amount of 10.3 g (91.8%) (HPLC purity 90.12%). MS (m / z): 892.2 (M + 1).

Step 4: Preparation of (11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E - (N-hydroxy) -carboxamidino] methylene} erythromycin A

To a solution of the product from step 3 (9 g) in a 1: 1 mixture = methanol: ethyl acetate (180 ml) was added a mixture of 10% Pd on charcoal (1.35 g) and 20% Pd (OH) ₂ (1.35 g) . The reaction mixture was hydrogenated in a shaker under a hydrogen pressure of 70 psi (4.9 kg / sq. Cm) for 48 hours. When TLC shows completion of the reaction, the mixture is suction filtered through a pad of celite. The filtrate was evaporated to dryness in vacuo to give 6.7 g of a solid, which was stirred with n-pentane (120 ml) and filtered to give the title compound in an amount of 5.8 g (71.6%) as a white solid ( HPLC purity 90.39%). MS (m / z) = 802.1 (M + 1).

A general procedure for the preparation of compounds of formula (I) in which R ₃ is H.

on which R ₃ = H,

T is as defined.

The reaction is carried out with (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-hydroxy) carboxamidino] methylene} erythromycin A in toluene in the presence of a base such as potassium hydride or potassium tert-butylate and an 18-crown-6-ether phase transfer catalyst with the corresponding racemic or enantiomerically pure side chain of the formula ZC * H (R ₁ ) -PQ, where Z represents bromide or an appropriate ester such as mesylate, tosylate or nosylate, and R ₁ , P and Q are as described at a temperature in the range of 25 to 35 ° C. by preparing the corresponding esterified compound (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-heteroaryl-heteroaryl- (RS), or (R), or (S) -alkoxy) -carboxamidino] methylene} erythromycin A.

Compound (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-heteroaryl-heteroaryl- (RS) , or (R) or (S) -alkoxy) carboxamidino] methylene} erythromycin A is oxidized by treatment under standard conditions with a Corey-Kim oxidizer (obtained from NCS and DMS) in dichloromethane at a temperature in the range from -50 to 10 ° C s preparation of the corresponding oxidized compound (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N- heteroaryl-heteroaryl- (RS), or (R), or (S) -alkoxy) carboxamidino] methylene} e erythromycin A.

Compound (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-2′-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-heteroaryl) is reacted -heteroaryl- (RS), or (R), or (S) -alkoxy) carboxamidino] methylene} erythromycin A with a silyl protecting agent such as pyridine hydrofluoride or aqueous hydrochloric acid in acetonitrile at a temperature in the range of 20 to 35 ° C to obtain a ketolide compound of formula (I), where R ₃ means N.

For compounds of formula (I), prepared as described above, where Q carries a substituent such as tert-butoxycarbonylamino, the tert-butoxycarbonyl group is deprotected by stirring the compound with trifluoroacetic acid in acetonitrile at a temperature of 0 to 35 ° C. for 1 hour. and subsequent purification, obtaining a ketolide compound of the formula (I).

For compounds of formula (I), prepared as described above, where Q carries a substituent such as O-benzyloxy, the benzyl group is deprotected by stirring the compound with 10% palladium on carbon under pressure of hydrogen in methanol at a temperature of from 25 to 35 ° C and subsequent purification to obtain a ketolide compound of the formula (I).

General procedure for the preparation of compounds of formula (I), wherein R ₃ is F

where R ₃ = F;

T is as defined.

Compound (11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-hydroxy) carboxamidino] methylene} erythromycin A in toluene in the presence of a suitable base such as potassium hydride or potassium tert-butylate and an 18-crown-6-ether phase transfer catalyst with the corresponding racemic or enantiomerically pure side chain of the formula ZC * H (R ₁ ) -PQ, where Z is a mesylate or nosylate ester, and R ₁ , P and Q are as described at a temperature in the range of 25 to 35 ° C., corresponding to this the ratified compound (11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {oxycarbonyl- [E- ( N-heteroaryl-heteroaryl- (RS), or (R), or (S) -alkoxy) carboxamidino] methylene} erythromycin A.

Compound (11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-heteroaryl-heteroaryl- (RS), or (R), or (S) -alkoxy) carboxamidino] methylene} erythromycin-A with a silyl protecting agent such as pyridine hydrofluoride or aqueous hydrochloric acid in acetonitrile at a temperature in the range from 20 to 35 ° C to obtain a ketolide compound of formula (I), where R ₃ denotes F.

For compounds of formula (I), prepared as described above, where Q carries a substituent such as tert-butoxycarbonylamino, the tert-butoxycarbonyl group is deprotected by stirring the compound with trifluoroacetic acid in acetonitrile at a temperature of 0 to 35 ° C. for 1 hour . and subsequent purification, obtaining a ketolide compound of the formula (I).

For compounds of formula (I), prepared as described above, where Q carries a substituent such as O-benzyloxy, the benzyl group is deprotected by stirring the compound with 10% palladium on carbon under pressure of hydrogen in methanol at a temperature of from 25 to 35 ° C and subsequent purification, obtaining a ketolide compound of the formula (I).

EXAMPLES

The following examples illustrate embodiments of the invention that are currently best known. However, it should be understood that the following examples are only typical or illustrative application of the principles of the present invention. Specialists in this field can develop numerous modifications and alternative compositions, methods and systems without deviating from the spirit and scope of the present invention. The appended claims are believed to encompass such modifications and arrangements. Thus, while the present invention has been described in detail above, the following examples relate to additional details related to what are currently considered the most practical and preferred variants of the present invention.

Example 1:

(11S, 21R) -3-Decladinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12,11- {oxycarbonyl- [EN- (5-pyrimidin-2-yl-isoxazole-3 -yl) methoxy] carboxamidino] methylene} erythromycin A

Step 1: Preparation of (11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [EN - (5-pyrimidin-2-yl-isoxazol-3-yl) methoxy] carboxamidino] methylene} erythromycin A.

To a stirred suspension of potassium hydride (1.46 g, 30% suspension in mineral oil), 18-crown-6-ether (0.660 g) in toluene (300 ml) was added, followed by (11S, 21R) -3-decadinosyl- 11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-2′-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-hydroxy) carboxamidino] methylene} erythromycin A ( 8 g) at 30 ° C. The mixture is stirred for 5 minutes. To the reaction mixture was added 2- (3-bromomethylisoxazol-5-yl) pyrimidine (2.9 g). The reaction mixture was stirred for 30 minutes. Quench the mixture by pouring it into a saturated aqueous solution of ammonium chloride (50 ml) with stirring. The mixture was extracted with ethyl acetate (250 ml × 2). The combined organic layer was dried over Na ₂ SO ₄ and evaporated in vacuo to give a wet mass which was purified by silica gel column chromatography (12 to 15% acetone in hexane) to give the title compound as the product from step 1 in an amount of 5 g with a yield of 53% as an off-white solid. MS (m / z): 961.4 (M + 1).

Stage 2: obtaining (11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12,11- {hydroxycarbonyl- [EN- (5-pyrimidin-2 -ilisoxazol-3-yl) methoxy] carboxamidino] methylene} erythromycin A.

Mixture of (11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [EN- (5 -pyrimidin-2-yl-isoxazol-3-yl) methoxy] carboxamidino] methylene} erythromycin A (5 g), obtained as described above in step 1, and a 70% solution of HF-pyridine (0.225 ml) in acetonitrile (50 ml) stirred at 30 ° C for 2 hours. in the atmosphere of N ₂ . Upon completion of the reaction, the reaction mixture was quenched by adding an aqueous solution of sodium bicarbonate (50 ml). The mixture was evaporated in vacuo to half the volume and water (20 ml) was added to the residue to obtain a suspension, which was filtered with suction. The solid was washed with water and then with ether to give the title compound of Example 1 in an amount of 3.1 g as a white solid in 71% yield. MS (m / z): 847.1 (M + 1).

The following examples were obtained by the procedure described above in example 1, using the corresponding side chains, which are shown below:

Formula I

Example No. T Side chain used
for joining Mp
(° C) Mass
(M + 1) 2

2- (5-bromomethylisoxazol-3-yl) pyrimidine 156-158 847.9 3

3- (2-bromomethylpyrimidin-5-yl) isoxazole 196-197 847.9 four

2-tert-butyloxycarbonylamino-6- (3-bromomethylisoxazol-5-yl) pyridine 215-217 861.9 5

2- (3-bromomethylisoxazol-5-yl) pyridine 193-194 846.9 6

2-tert-butyloxycarbonylamino-6- (5-bromomethyl-1,3,4-thiadiazol-2-yl) pyridine 230-232 879.0 7

2- (5-bromomethyl-1,3,4-thiadiazol-2-yl) pyrimidine 192-194 864.9 8

2- (5-bromomethyl-1,3,4-thiadiazol-2-yl) pyrazine 223-225 864.9 9

2-tert-butyloxycarbonylamino-5- (5-bromomethyl-1,3,4-thiadiazol-2-yl) pyridine 202-204 879.0 10

2- (5-bromomethyl-1,3,4-thiadiazol-2-yl) pyridine 207-210 864.0 eleven

2- (3-bromomethylisoxazol-5-yl) pyrazine 196-197 847.0 12

2-tert-butyloxycarbonylamino-5- (5-bromomethyl-1,3,4-thiadiazol-2-yl) pyrazine 178-180 879.0 13

6-tert-butyloxycarbonylamino-2- [5-bromomethyl-1,3,4-thiadiazol-2-yl] pyrimidine 210-214 879.0 fourteen

2- (2-bromomethylpyrimidin-5-yl) pyrazine 169-171 858.1 fifteen

3-tert-butyloxycarbonylamino-1- (5-bromomethyl-1,3,4-thiadiazol-2-yl) benzene 180-185 878.1 16

2-di- (tert-butyloxycarbonyl) amino-6- (2-bromomethylpyridin-6-yl) pyridine 150-152 872.0 17

6-tert-butyloxycarbonylamino-2- (3-bromomethylisoxazol-5-yl) pyrimidine - 862.1

Example 18:

(11S, 21R) -3-Decladinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12,11- {hydroxycarbonyl- [EN- [1- (5-pyrimidin-2- yl-1,3,4-thiadiazol-2-yl) - (S) -ethoxy] carboxamidino] methylene} erythromycin A

Step 1: Preparation of (11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [EN - [1- (5-pyridin-2-yl-1,3,4-thiadiazol-2-yl) - (S) -ethoxy] carboxamidino] methylene} erythromycin A.

To a stirred solution of (11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-hydroxy) carboxamidino] methylene} erythromycin A (3.5 g) in toluene (50 ml) add potassium hydride (0.07 g, 30% suspension in mineral oil), 18-crown-6-ether (0, 2 g) and then (R) -2- (5- (1-nosyloxyethyl) -1,3,4-thiadiazol-2-yl) pyridine (1.5 g) at a temperature of 0 ° C. The reaction mixture was stirred for 4 hours. Quench the mixture by pouring it into a saturated aqueous solution of ammonium chloride (50 ml). The mixture was extracted with ethyl acetate (100 ml × 2). The combined organic layer was dried over Na ₂ SO ₄ , evaporated in vacuo to give the crude compound - product from step 1 in an amount of 4.0 g (92%) as a syrup, which was used as is in the next step. MS (m / z): 991.3 (M + 1).

Step 2: Preparation of (11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12,11- (hydroxycarbonyl- [EN- [1- (5- pyridin-2-yl-1,3,4-thiadiazol-2-yl) - (S) -ethoxy] carboxamidino] methylene} erythromycin A

The mixture of the product from step 1 (11S, 21R) -3-decadinosyl-11,12-dideoxy-2-fluoro-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [ EN- [1- (5-pyridin-2-yl-1,3,4-thiadiazol-2-yl) - (S) -ethoxy] carboxamidino] methylene} erythromycin A (4 g) and 70% HF-pyridine solution (0.400 ml) in acetonitrile (40 ml) was stirred at 30 ° C for 2 hours. in the atmosphere of N ₂ . Upon completion of the reaction, the reaction mixture was quenched by adding an aqueous solution of sodium bicarbonate (50 ml). The mixture was evaporated in vacuo to half volume. Water (20 ml) was added to the crude product to give a suspension, which was filtered with suction. The solid is washed with water and then with ether, obtaining a crude compound, which is purified by recrystallization using a mixture of ethyl acetate-methanol (1: 4) to obtain 2-fluoro-ketolide compounds of the invention in an amount of 1.3 g (37%) as a white solid substances. Retention time 21.29 (HPLC purity 91.66%), mp = 133-135 ° C, MS (m / z): 877.1 (M + 1).

The following examples were obtained according to the procedure described in example 18, using the corresponding analogues of para-nitrophenylsulfonyl (nosyl) with the corresponding side chains:

Example No. T Side chain used to attach Mp
(° C) Mass
(M + 1) 19

(S) -2-tert-butyloxycarbonylamino-6- [5- (1-methanesulfonyloxyethyl) -1,3,4-thiadiazol-2-yl] pyridine 208-210 893.1 twenty

(R) -2-tert-butyloxycarbonylamino-6- [5- (1-methanesulfonyloxyethyl) -1,3,4-thiadiazol-2-yl] pyridine 230-232 893.1 21

(R) -2- [5- (1-methanesulfonyloxyethyl) -1,3,4-thiadiazol-2-yl] pyrimidine 168-170 879.1 22

(R) - [5- (1-nosyloxyethyl) -1,3,4-thiadiazol-2-yl] pyrazine 232-234 879.1 23

(R) - [3- (1-nosyloxyethyl) isoxazol-5-yl] pyrimidine 170-172 861.1 24

(R) -3-tert-butyloxycarbonylamino [5- (1-nosyloxyethyl) -1,3,4-thiadiazol-2-yl] benzene 244-245 892.0 25

(R) -2- [3- (1-nosyloxyethyl) isoxazol-5-yl] pyridine 194-196 860.1 26

(R) -3- [2- (1-nosyloxyethyl) pyrimidin-5-yl] isoxazole 193-195 861.1 27

(S) -3- [2- (1-nosyloxyethyl) pyrimidin-5-yl] isoxazole 152-154 861.1 28

(R) -2-tert-butyloxycarbonylamino-6- [3- (1-nosyloxyethyl) isoxazol-5-yl] pyridine 205-207 875.1 29th

(RS) -2- [5- (1-nosyloxypropyl) thiadiazol-2-yl] pyridine 208-210 891.3 thirty

210-212 891.3

Example 31:

(11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11- {oxycarbonyl- [EN- [1- (5-pyridin-2-yl-1, 3,4-thiadiazol-2-yl) - (RS) ethoxy] carboxamidino] methylene} erythromycin A

Stage 1: obtaining (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [EN- [1- (5-pyridine -2-yl-1,3,4-thiadiazol-2-yl- (RS) ethoxy] carboxamidino] methylene} erythromycin A

To a stirred solution of (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-hydroxy) carboxamidino] methylene } erythromycin A (1.5 g) in toluene (20 ml) add potassium hydride (0.3 g, 30% suspension in mineral oil), 18-crown-6-ether (0.1 g), and then (RS ) -2- [5- (1-bromoethyl) -1,3,4-thiadiazol-2-yl] pyridine (0.7 g) at a temperature of 30 ° C. The reaction mixture was stirred for 30 minutes. Quench the mixture by pouring it into a saturated aqueous solution of ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (100 ml × 2). The combined organic layer was dried over Na ₂ SO ₄ , evaporated in vacuo to give a wet mass, which was purified by silica gel column chromatography (15% acetone: hexane) to give the product from stage 1 in an amount of 1.5 g (80%) as off-white solid. MS (m / z): 975.3 (M ⁺ ).

Step 2: Preparation of (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [EN- [1- (5-pyridin-2-yl-1,3,4-thiadiazol-2-yl) - (RS) -ethoxycarboxamidino] methylene} erythromycin A

To a stirred solution of N-chlorosuccinimide (1.5 g) in dichloromethane (75 ml) was added dimethyl sulfide (2 ml) at -10 ° C. The reaction mixture was stirred at -10 ° C for 30 minutes. The product from step 1 (1.5 g) dissolved in dichloromethane (25 ml) was added to the reaction mixture at -40 ° C. The resulting reaction mixture was stirred at -40 ° C for 3 hours. Triethylamine (5 ml) was added and the mixture was stirred overnight at 30 ° C. The reaction mixture was poured into saturated aqueous sodium bicarbonate (20 ml) and the mixture was extracted with dichloromethane (50 ml × 2). The combined organic layer was dried over Na ₂ SO ₄ and evaporated in vacuo to give a wet mass, which was purified by silica gel column chromatography (12% acetone: hexane) to obtain the product from stage 2 as a semi-solid in an amount of 1.2 g (80 %). MS (m / z): 973.4 (M ⁺ ).

Step 3: Preparation of (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11- {hydroxycarbonyl- [EN- [1- (5-pyridin-2- yl-1,3,4-thiadiazol-2-yl) - (RS) ethoxy] carboxamidino] methylene} erythromycin A

A mixture of the product from step 2 (1.2 g) and a 70% solution of HF-pyridine (0.2 ml) in acetonitrile (20 ml) was stirred at 30 ° C for 2 hours. in the atmosphere of N ₂ . An aqueous solution of sodium bicarbonate (10 ml) was added and the mixture was extracted with dichloromethane (50 ml × 2). The combined organic layer was dried over sodium sulfate and evaporated in vacuo to give a crude mass. The crude mass was purified by silica gel column chromatography (3% MeOH in CHCl ₃ ) to give 0.7 g (59%) of the title compound as an off-white solid.

HPLC analysis showed the presence of a mixture with a ratio of 44.97 (at 21.42 min.) And 52.09 (at 25.25 min.). Mp = 135-137 ° C, MS (m / z): 859.3 (M ⁺ ).

Example 32:

Isolation of (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11- {oxycarbonyl- [EN- [1- (5-pyridin-2-yl-1 , 3,4-thiadiazol-2-yl) - (R) -ethoxy] carboxamidino] methylene} erythromycin A

Separate 0.5 g of the diastereomeric mixture obtained in Example 31 by preparative HPLC using a VMC-ODS-A column, mobile phase 0.05 ammonium acetate buffer: acetonitrile (60:40 ratio), the pH of which is adjusted to 7 with ammonia and acetic acid acid, and a flow rate of 18 ml / min., UV detection at 215 nm.

The title compound was obtained with a retention time of 21.39 (HPLC purity 93.20%), mp. = 140-142 ° C, MS (m / z): 860.1 (M + 1).

Example 33:

Isolation of (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11- {oxycarbonyl- [EN- [1- (5-pyridin-2-yl-1 , 3,4-thiadiazol-2-yl) - (S) -ethoxy] carboxamidino] methylene} erythromycin A

Using similar HPLC conditions, the title compound is obtained with a retention time of 25.11 (HPLC purity 98.52%), mp. = 128-130 ° C, MS (m / z): 860.1 (M + 1).

The following examples were obtained using the procedure described in example 31 and using appropriate bromine-containing analogs of the corresponding side chains, followed by separation of the diastereomeric mixture by preparative HPLC.

Example No. T Side chain used
for joining Mp
(° C) Mass
(M + 1) 34

(RS) -2- [5- (1-bromoethyl) isoxazol-3-yl] pyridine 220-221 842.9 35

216-218 842.9 36

118-120 842.9 37

(RS) -2- [3- (1-bromoethyl) isoxazol-5-yl] pyrimidine 116-117 843.9 38

241-243 943.9 39

121-123 843.9 40

(RS) -2- [3- (1-bromoethyl) isoxazol-5-yl] pyridine 210-212 842.9 41

138-140 842.9 42

(RS) -2- [3- (1-bromopropyl) isoxazol-5-yl] pyridine 112-114 857.0 43

174-176 857.0 44

(RS) - [5- (1-bromoethyl) -1,3,4-thiadiazol-2-yl] pyrimidine 173-175 861.1 45

204-206 861.1 46

170-172 861.1 47

(RS) -2-tert-butyloxycarbonylamino-5- [5- (1-bromoethyl) -1,3,4-thiadiazol-2-yl] pyridine 164-166 875.0 48

170-172 875.1 49

138-140 875.1 fifty

(RS) - [5- (1-bromoethyl) -1,3,4-thiadiazol-2-yl] pyrazine 206-208 861.1 51

178-180 861.1 52

206-208 861.1 53

(RS) -2- [5- (1-bromoethyl) -1,3,4-oxadiazol-2-yl] pyridine 120-122 843.1

The method of obtaining, alternative to example 33:

(11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11- {oxycarbonyl- [EN- [1- (5-pyridin-2-yl-1, 3,4-thiadiazol-2-yl) - (S) -ethoxy] carboxamidino] methylene} erythromycin A

Stage 1: obtaining (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [EN- [1- (5-pyridine -2-yl-1,3,4-thiadiazol-2-yl) - (S) -ethoxy] carboxamidino] methylene} erythromycin A

To a stirred solution of (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-2'-O-triethylsilyl-12,11- {hydroxycarbonyl- [E- (N-hydroxy) carboxamidino] methylene } erythromycin A (35.0 g) in toluene (350 ml), 18-crown-6-ether (1.96 g) was successively added followed by potassium tert-butylate (5.6 g) at 30 ° C. The blue suspension is stirred for 10 minutes to obtain a clear solution. To this solution was added at a temperature of 30 ° C (R) -2- [5- (1-nosyloxyethyl) -1,3,4-thiadiazol-2-yl] pyridine (19.4 g, obtained from methyl D-lactate ) as a solid and then toluene (70 ml). The reaction mixture was stirred for 30 minutes. at 30 ° C. The reaction was quenched with a 3% aqueous solution of ammonium chloride (200 ml) when TLC showed complete conversion of the starting material. (TLC system - hexane: ethyl acetate: diethylamine = 5: 5: 2). The mixture was extracted with ethyl acetate (250 ml × 2). The combined organic layer was washed with brine and dried over Na ₂ SO ₄ , evaporated in vacuo to give a green mass in the form of a yellow foam in an amount of 47 g, which was used as is for the next reaction. MS (M ⁺ ) = 975.4 HPLC chemical purity 73.7%, diastereomeric purity 99.42%.

Stage 2: obtaining (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-2'-O-triethylsilyl-12,11- {oxycarbonyl- [Ε-Ν- [ 1- (5-pyridin-2-yl-1,3,4-thiadiazol-2-yl) - (S) -ethoxy] carboxamidino] methylene} -erythromycin A.

To a stirred solution of N-chlorosuccinimide (18.02 g) in dichloromethane (180 ml) was added dimethyl sulfide (11.2 ml) at a temperature of from -20 to -15 ° C. The reaction mixture was stirred at −20 to −15 ° C. for 30 minutes. The product from step 1 (46.7 g) dissolved in dichloromethane (300 ml) was added to the reaction mixture at a temperature of -50 to -40 ° C using a dropping funnel. The resulting reaction mixture was stirred at a temperature of from -40 to -35 ° C for 3 hours. Triethylamine (15.6 ml) was added at -40 ° C and stirred at 30 ° C until the reaction mixture became clear. Ethyl acetate (880 ml) was added to the reaction mixture with stirring, followed by a 0.5N aqueous sodium hydroxide solution (410 ml). After 30 minutes mixing separated layers. Rinse them successively with water (410 ml), then with brine (410 ml). The organic layer was dried over Na ₂ SO ₄ and evaporated in vacuo to give a yellow foam in an amount of 49 g, which was added to the next reaction without purification. MS (M ⁺ ): 973.3, HPLC chemical purity 79.35%, chiral purity 97.82%.

Step 3: Preparation of (11S, 21R) -3-decadinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11- {hydroxycarbonyl- [EN- [1- (5-pyridin-2- yl-1,3,4-thiadiazol-2-yl) - (S) -ethoxy] carboxamidino] methylene} erythromycin A.

A mixture of the product from step 2 (48 g) and a 2N aqueous solution of hydrochloric acid (50 ml) in acetonitrile (125 ml) was stirred at 30 ° C for 4 hours. The clear red solution is diluted with water (300 ml) and approximately 125 ml of solvent volume is removed in vacuo at a temperature below 55 ° C. The reaction mixture was cooled to 25 ° C and extracted with ethyl acetate (150 ml). The aqueous layer was made basic using an aqueous solution of potassium carbonate (100 ml, 18% w / v). The suspension was extracted with ethyl acetate (250 ml × 2). The organic layer was washed with brine (150 ml) and concentrated in vacuo to give a light brown foam in an amount of 42 g. The crude foam was purified using warm (40 ° C) ethanol (84 ml). The suspension is filtered with suction at 10 ° C. The filter cake was washed with chilled ethanol (10 ml × 2). Drying the solid gives a light yellow powder in an amount of 22.3 g with 52% yield after three stages. MS (M ⁺ ): 859.3; HPLC purity 96.48%; so pl. = 135-137 ° C.

The following examples were obtained using the procedure described above for the preparation of Example 33 and using either the appropriate para-nitrophenylsulfonyl (nosyl) or methanesulfonic ester analogues of the corresponding side chains.

Example No. T Side chain used to attach Mp
(° C) Mass
(M + 1) 54

(R) -2-tert-butyloxycarbonylamino-6- [5- (1-methanesulfonyloxyethyl) -1,3,4-thiadiazol-2-yl] pyridine 197-200 875.0 55

(S) -2-tert-butyloxycarbonylamino-6- [5- (1-methanesulfonyloxyethyl) -1,3,4-thiadiazol-2-yl] pyridine 205-207 875.1 56

(R) -3-tert-butyloxycarbonylamino [5- (1-nosyloxyethyl) -1,3,4-thiadiazol-2-yl] benzene 242-244 874.0 57

(R) -2-benzyloxy-6- [5- (1-nosyloxyethyl) -1,3,4-thiadiazol-2-yl] pyridine 168-170 876.0 58

(R) -3- [2- (1-nosyloxyethyl) pyrimidin-5-yl] isoxazole 172-174 843.1 59

(R) -2-tert-butyloxycarbonylamino-6- [3- (1-nosyloxyethyl) isoxazol-5-yl] pyridine 170-172 858.0 60

(R) -4-benzyloxy-2- [5- (1-nosyloxyethyl) isoxazol-2-yl] pyridine 150-152 876.0 61

(RS) -2- [5- (2-tert-butyldimethylsilyloxy-1-nosyloxyethyl) -1,3,4-thiadiazol-2-yl] pyridine 96-105 876.0 62

98-108 876.0 63

(RS) -2- [5- (1-nosyloxypropyl) thiadiazol-2-yl] pyridine 140-144 874.0 64

206-208 874.0 65

186-188 874.0

BIOLOGICAL PROTOCOLS AND ACTIVITIES

In vitro Evaluation of the Compounds of the Invention

The antibacterial activity of the compounds of the invention is evaluated by determining the minimum inhibitory concentration (MIC) according to the standard CLSI agar dilution method. The media used for the pre-culture and main culture are tryptic soy broth (Difco) and Mueller-Hinton (Difco) media, respectively. Mueller-Hinton agar is supplemented with 5% sheep blood for streptococci and pneumococci and hemoglobin, as well as NAD (nicotinamide adenine dinucleotide) for Haemophilus influenzae. Overnight cultures were diluted with physiological saline with buffer (pH 7.2) to a final cell density of 5 × (10 ⁶ -10 ⁷ ) CFU / ml, and each bacterial suspension was applied using a replicator (Denley Multipoint Inoculator, UK) on a series of agar plates Muller-Hinton containing antibacterial agents with various concentrations. The final inoculum has approximately 10 ⁴ CFU / spot. The plates are incubated for 18 hours. at 37 ° C. MIC is defined as the lowest concentration of an antibacterial agent that inhibits the development of visible microbial growth on agar.

The compounds of the invention inhibit the growth of these bacteria with MICs in the range of about 0.007-0.25 μg / ml (S. pneumoniae sensitive strains, Telithromycin MICs 0.007-0.015 μg / ml), 0.007-2.0 μg / ml (S. pneumoniae strains mef, MIC of telithromycin 0.015-1.0 μg / ml), 0.007-2.0 μg / ml (S. pneumoniae ermb strains, MIC of telithromycin 0.007-0.50 μg / ml), 0.12 - (> 16) μg / ml (S. pneumoniae 3773, high level of ermb strain, MIC of telithromycin 4.0 μg / ml), 0.12 - (> 16) μg / ml (S.pyogene 3530, high level of ermb strain, MIC of telithromycin 16.0 μg / ml), 1-8 μg / ml (H influenzae, MIC of Telithromycin 4.0-8.0 μg / ml).

In vivo evaluation of compounds of the invention

The in vivo efficacy of the compounds of the invention is assessed by determining the ED ₅₀ when the compounds are orally administered to a group of mice (6 mice per dose-specific group) infected intraperitoneally (5 × 10 ⁷ -1 × 10 ⁸ CFU / mouse) S. pneumoniae 3773. Two doses the compounds of the invention and telithromycin are administered 1 hour and 4 hours after infection. On the seventh day, the percentage of surviving animals in groups with different doses is used to determine the ED ₅₀ (dose 50% protection of infected mice).

Some of the compounds of the invention exhibit superior oral efficacy against S. pneumoniae 3773 infection in mice (ED ₅₀ 6.25-50 mg / kg) compared with telithromycin (ED ₅₀ 75-100 mg / kg).

Claims (32)

1. The compound of formula (I) or its pharmaceutically acceptable salt or stereoisomer,

Where
T is —C * H (R ₁ ) —PQ;
R ₁ is C ₁ -C ₆ alkyl optionally substituted with OH or C ₁ -C ₆ alkoxy;
P represents a 5- or 6-membered heteroaryl ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;
Q represents a 5- or 6-membered heteroaryl ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur; optionally substituted with one or more substituents selected from an amino group and a hydroxy group;
P is attached to Q via a carbon-carbon bond; and
R ₃ represents a hydrogen atom. 2. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is C ₁ -C ₆ alkyl optionally substituted with OH or C ₁ -C ₆ alkoxy;
R ₃ represents a hydrogen atom;
P represents a 5- or 6-membered heteroaryl ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur;
Q represents a 5- or 6-membered heteroaryl ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; optionally substituted with one or more substituents selected from an amino group and a hydroxy group; and
P is attached to Q via a carbon-carbon bond. 3. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is C ₁ -C ₆ alkyl;
R ₃ represents a hydrogen atom;
P represents a 5- or 6-membered heteroaryl ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;
Q represents a 5- or 6-membered heteroaryl ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur; optionally substituted with one or more substituents selected from an amino group and a hydroxy group; and
P is attached to Q via a carbon-carbon bond. 4. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is C ₁ -C ₆ alkyl;
R ₃ represents a hydrogen atom;
P represents a 5- or 6-membered heteroaryl ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur;
Q represents a 5- or 6-membered heteroaryl ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; optionally substituted with one or more substituents selected from an amino group and a hydroxy group; and
P is attached to Q via a carbon-carbon bond. 5. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is methyl;
R ₃ represents a hydrogen atom;
P represents a 5- or 6-membered heteroaryl ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;
Q represents a 5- or 6-membered heteroaryl ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur; optionally substituted with one or more substituents selected from an amino group and a hydroxy group; and
P is attached to Q via a carbon-carbon bond. 6. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is methyl;
R ₃ represents a hydrogen atom;
P represents a 5- or 6-membered heteroaryl ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur;
Q represents a 5- or 6-membered heteroaryl ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; optionally substituted with one or more substituents selected from an amino group and a hydroxy group; and
P is attached to Q via a carbon-carbon bond. 7. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is C ₁ -C ₆ alkyl optionally substituted with OH or C ₁ -C ₆ alkoxy;
R ₃ represents a hydrogen atom;
P is isoxazole, pyridine, pyrimidine or thiadiazole;
Q is pyridine, pyrimidine, isoxazole or thiadiazole, optionally substituted with one or more substituents selected from an amino group and a hydroxy group; and
P is attached to Q via a carbon-carbon bond. 8. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is C ₁ -C ₆ alkyl;
R ₃ represents a hydrogen atom;
P is isoxazole, pyridine, pyrimidine or thiadiazole;
Q is pyridine, pyrimidine, isoxazole or thiadiazole, optionally substituted with one or more substituents selected from an amino group and a hydroxy group; and
P is attached to Q via a carbon-carbon bond. 9. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is methyl;
R ₃ represents a hydrogen atom;
P is isoxazole, pyridine, pyrimidine or thiadiazole;
Q is pyridine, pyrimidine, isoxazole or thiadiazole, optionally substituted with one or more substituents selected from an amino group and a hydroxy group; and
P is attached to Q via a carbon-carbon bond. 10. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is C ₁ -C ₆ alkyl optionally substituted with OH or C ₁ -C ₆ alkoxy;
R ₃ represents a hydrogen atom;
P is isoxazole, pyridine, pyrimidine or thiadiazole;
Q is pyridine, pyrimidine, isoxazole or thiadiazole; and
P is attached to Q via a carbon-carbon bond. 11. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is C ₁ -C ₆ alkyl;
R ₃ represents a hydrogen atom;
P is pyrimidine, isoxazole, pyridine or thiadiazole;
Q is pyridine, pyrimidine, isoxazole or thiadiazole; and
P is attached to Q via a carbon-carbon bond. 12. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is methyl;
R ₃ represents a hydrogen atom;
P is pyrimidine, isoxazole, pyridine or thiadiazole;
Q is isoxazole, pyridine, pyrimidine or thiadiazole; and
P is attached to Q via a carbon-carbon bond. 13. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is C ₁ -C ₆ alkyl;
P is thiadiazole;
Q is pyridine; and
P is attached to Q via a carbon-carbon bond; and
R ₃ represents a hydrogen atom. 14. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is C ₁ -C ₆ alkyl;
P is thiadiazole;
Q is pyrimidine; and
P is attached to Q via a carbon-carbon bond; and
R ₃ represents a hydrogen atom. 15. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is methyl;
P is thiadiazole;
Q is pyridine; and
P is attached to Q via a carbon-carbon bond; and
R ₃ represents a hydrogen atom. 16. The compound according to claim 1, in which:
T is —C * H (R ₁ ) —PQ;
R ₁ is methyl;
P is thiadiazole;
Q is pyrimidine; and
P is attached to Q via a carbon-carbon bond; and
R ₃ represents a hydrogen atom. 17. The compound or its pharmaceutically acceptable salt or stereoisomer selected from:
the compounds of formula (I), where T is (RS) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (R) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (RS) - [3- (pyridin-2-yl) isoxazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (R) - [3- (pyridin-2-yl) isoxazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [3- (pyridin-2-yl) isoxazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (RS) - [5- (pyrimidin-2-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (R) - [5- (pyrimidin-2-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [5- (pyrimidin-2-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (R) - [5- (pyridin-2-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [5- (pyridin-2-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (R) - [5- (pyridin-2-yl) isoxazol-3-yl] -CH (C ₂ H ₅ ) - and R ₃ is H;
the compounds of formula (I), where T is (S) - [5- (pyridin-2-yl) isoxazol-3-yl] -CH (C ₂ H ₅ ) - and R ₃ is H;
compounds of formula (I), where T is (RS) - [2- (pyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (R) - [2- (pyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [2- (pyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [2- (2-aminopyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;
compounds of formula (I), where T is (R) - [2- (2-aminopyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;
compounds of formula (I), where T is (RS) - [2- (2-aminopyridin-5-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;
compounds of formula (I), where T is (S) - [2- (2-aminopyridin-5-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;
compounds of formula (I), where T is (R) - [2- (2-aminopyridin-5-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;
compounds of formula (I), where T is (RS) - [2- (pyrazin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (R) - [2- (pyrazin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [2- (pyrazin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (RS) - [2- (pyridin-2-yl) -1,3,4-oxadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [2- (3-aminophenyl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [2- (2-hydroxypyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;
compounds of formula (I), where T is (S) - [5- (isoxazol-3-yl) pyrimidin-2-yl] -CH (CH ₃ ) - and R ₃ is H;
the compounds of formula (I), where T is (S) - [5- (2-aminopyridin-6-yl) isoxazol-3-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [2- (4-hydroxypyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;
compounds of formula (I), where T is (R) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₂ OH) - and R ₃ is H;
compounds of formula (I), where T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₂ OH) - and R ₃ is H;
compounds of formula (I), where T is (RS) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (C ₂ H ₅ ) - and R ₃ is H ;
compounds of formula (I), where T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (C ₂ H ₅ ) - and R ₃ is H ; and
the compounds of formula (I), where T is (R) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (C ₂ H ₅ ) - and R ₃ is H . 18. The compound or its pharmaceutically acceptable salt or stereoisomer selected from:
compounds of formula (I), where T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [2- (pyrimidin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [2- (2-aminopyridin-6-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;
compounds of formula (I), where T is (S) - [2- (2-aminopyridin-5-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₃ ) - and R ₃ is H ;
compounds of formula (I), where T is (S) - [5- (isoxazol-3-yl) pyrimidin-2-yl] -CH (CH ₃ ) - and R ₃ is H;
compounds of formula (I), where T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (CH ₂ OH) - and R ₃ is H; and
compounds of formula (I), where T is (S) - [2- (pyridin-2-yl) -1,3,4-thiadiazol-5-yl] -CH (C ₂ H ₅ ) - and R ₃ is H . 19. The compound of formula (I), in which:

T is —C * H (R ₁ ) —PQ;
R ₁ is methyl;
P is 1,3,4-thiadiazole;
Q is pyridin-2-yl or pyrimidin-2-yl; and
P is attached to Q via a carbon-carbon bond; and
R ₃ represents a hydrogen atom. 20. The compound representing

or a pharmaceutically acceptable salt thereof. 21. The compound representing

or a pharmaceutically acceptable salt thereof. 22. The method of obtaining the compounds of formula (15-f)

including:
(i) reacting a compound of formula (15-a) with hydrazine hydrate to give a compound of formula (15-b);

(ii) reacting a compound of formula (15-b) with 2-picolinic acid to give a compound of formula (15-c);

(iii) cyclization of a compound of formula (15-c) to obtain a compound of formula (15-d); and

(iv) deprotecting a compound of formula (15-d) to give a compound of formula (15-e);

(v) reacting a compound of formula (15-e) with p-nitrophenylsulfonyl chloride to give a compound of formula (15-f). 23. The method of obtaining the compounds of formula (16-d)

including:
(i) reacting pyrimidine-2-carbonyl chloride with a compound of formula (15-b) to obtain a compound of formula (16-a);

(ii) cyclization of a compound of formula (16-a) to give a compound of formula (16-b);

(iii) deprotecting a compound of formula (16-b) to give a compound of formula (16-c); and

(iv) reacting a compound of formula (16-c) with p-nitrophenylsulfonyl chloride to give a compound of formula (16-d). 24. The method of obtaining the compounds of formula (18th)

where P is a 5- or 6-membered heteroaryl ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;
Q represents a 5- or 6-membered heteroaryl ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur; optionally substituted with one or more substituents selected from an amino group and a hydroxy group;
P is attached to Q via a carbon-carbon bond,
including,
(i) reacting a compound of formula (18-a) with a compound of formula (18-b) in the presence of a base or in the presence of a phase transfer catalyst to obtain a compound of formula (18-c)

Z = Br or R-SO ₂ —O—, where R = methyl, nitrophenyl, and
P and Q = as defined;

(ii) oxidizing a compound of formula (18-c) to obtain a compound of formula (18-d), and

(iii) reacting a compound of formula (18-d) with a silyl deprotecting agent to obtain a compound of formula (18th). 25. An antibacterial pharmaceutical composition comprising a compound according to any one of paragraphs. 1-21 or a pharmaceutically acceptable salt or stereoisomer thereof. 26. The pharmaceutical composition according to p. 25, where the composition is administered parenterally or orally. 27. A method of treating a subject with an infection caused by a microorganism, comprising administering to a subject in need of a therapeutically effective amount of a compound according to any one of paragraphs. 1-21 or a pharmaceutically acceptable salt or stereoisomer thereof. 28. A method for prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by a microorganism, a prophylactically effective amount of a compound according to any one of paragraphs. 1-21 or a pharmaceutically acceptable salt or stereoisomer thereof. 29. A method of treating a subject with an infection caused by a microorganism, comprising administering to a subject in need of a pharmaceutical composition according to claim 25. 30. A method for the prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by a microorganism, a pharmaceutical composition according to claim 25. 31. The method according to p. 27-30, where the microorganism is a bacterium. 32. The use of compounds according to any one of paragraphs. 1-21 for the manufacture of a medicament for the treatment of an infection caused by a microorganism.